Resorcinol derivatives

ABSTRACT

The present invention relates to certain resorcinol derivatives and their use as skin lightening agents.

[0001] This application claims priority from U.S. provisionalapplication Serial No. 60/234,468, filed Sep. 21, 2000, which isincorporated herein by reference.

FIELD OF THE INVENTION

[0002] The present invention relates to certain resorcinol derivativesand their use as skin lightening agents.

BACKGROUND OF THE INVENTION

[0003] The terms “lightening agent” and “depigmentation agent” are usedinterchangeably throughout this document.

[0004] Skin color in humans arises from a complex series of cellularprocesses that are carried out within a unique population of cellscalled melanocytes. Melanocytes are located in the lower part of theepidermis, and their function is to synthesize a pigment, melanin, whichprotects the body from the damaging effects of ultraviolet radiation.

[0005] When skin is exposed to ultraviolet radiation, such as thatcontained in sunlight, melanocytes increase their synthesis of melanin.Melanin is deposited in melanosomes, which are vesicles found within thecell. The melanosomes are extruded from the cell and carried to thesurface of the skin by keratinocytes, which internalize themelanin-containing melanosomes. The end result is that the visiblelayers of the skin exhibit a brown color typically known as a “tan”. Thedarkness of the color observed in the skin is proportionate to theamount of melanin synthesized by melanocytes and transferred to thekeratinocytes.

[0006] The mechanism by which skin pigmentation is formed,melanogenesis, is particularly complex and schematically involves thefollowing main steps: Tyrosine→L-Dopa→Dopaquinone→Dopachrome→Melanins.The first two reactions in this series are catalyzed by the enzymetyrosinase. The activity of tyrosinase is promoted by the action ofα-melanocyte stimulating hormone or UV rays. It is well established thata substance has a depigmenting effect if it acts directly on thevitality of the epidermal melanocytes where melanogenesis normallyoccurs and/or if it interferes with one of the stages in melaninbiosynthesis. The active compounds that are employed in the variousmethods and compositions of this invention inhibit tyrosinase and thusinhibit or decrease melanin biosynthesis.

[0007] There is a strong demand for agents that enable acquireddeposition sites, such as spots or freckles, to be restored to a normalskin color. For this purpose, a variety of agents and methods have beendeveloped and put on the market. Examples of such methods are (a) amethod wherein vitamin C (L-ascorbic acid) having good reducing abilityis administered orally in large amounts, (b) a method whereinglutathione is administered parenterally; (c) a method wherein aperoxide, such as hydrogen peroxide, zinc peroxide, sodium peroxide andthe like, is administered: and (d) a method wherein vitamin C orcysteine is administered topically in the form of an ointment, cream,lotion or the like. Vitamin C has a problem with respect to stabilityand becomes so unstable in water-containing systems that they will causechanges in odor and color. Thiol compounds such as glutathione andcysteine do not exhibit a satisfactory depigmental effect since thedevelopment of the effect is very slow.

[0008] The substances in widest use at the present time as depigmentorsare, in particular, hydroquinone and its derivatives, particularly itsethers such as hydroquinone monomethyl ether. These compounds, whileeffective, are known to produce side effects that can be dangerous.Hydroquinone, use of which is limited to a concentration of 2%, is bothirritating and cytotoxic to the melanocyte.

[0009] U.S. Pat. No. 4,526,179 refers to certain hydroquinone fattyesters that have good activity and are less irritating and more stablethan hydroquinone.

[0010] Japanese Patent Application No. 27909/86 refers to otherhydroquinone derivatives that do not have the drawbacks of hydroquinonebut that have relatively poor efficacy.

[0011] U.S. Pat. No. 5,449,518 refers to 2,5-dihydoxyphenyl carboxylicacid derivatives as skin depigmentation agents.

[0012] European Patent Application EP 341,664A1 refers to certainresorcinol derivatives as tyrosinase inhibitors and skin depigmentationagents.

[0013] PCT International Publication WO 99/15148 refers to certainresorcinol derivatives as tyrosinase inhibitors and skin depigmentationagents.

[0014] The use of topical depigmention agents that have good efficacyand are harmless is particularly desirable for treating the following:regional hyperpigmentation caused by melanocytic hyperactivity, such asidiopathic melasma occurring either during pregnancy (mask of pregnancyor chloasma) or secondary to estrbgen-progesterone contraception; localhyperpigmentation caused by benign melanocytic hyperactivity andproliferation such as lentigo senilis or liver spots; accidentalhyperpigmentation such as post-lesional photosensitization and scarring;and certain forms of leukoderma such as vitiligo where, if the injuredskin cannot be repigmented, the residual zones of normal skin aredepigmented to impart a homogeneous white color to the entire skin.

SUMMARY OF INVENTION

[0015] The resorcinol derivatives of formula I, which are defined belowand used in the various methods and compositions of this invention, areuseful in the treatment of the foregoing dermatological conditions aswell as other dermatological conditions, some of which are referred tolater in this document, for which the subject being treated desires, formedicinal or cosmetic purposes, to lighten or reduce the pigmentation ofthe skin affected by the condition.

[0016] The resorcinol derivatives of formula I are also useful for thetreatment of inflammatory disorders such as psoriasis, dermatitis andacne, and for the treatment of dandruff.

[0017] The invention thus provides a compound of formula I:

[0018] or a pharmaceutically acceptable salt thereof, wherein:

[0019] R is a (C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substitutedby —N(R¹)CONR²R³ wherein R¹ and R² are independently selected fromhydrogen, (C₁-C₆)alkyl, and, aryl(C₁-C₆)alkyl and R³ is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; —N(R⁴)COR⁵ wherein R⁴ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-, or OH and R⁵ is(C₇-C₁₀)alkyl, aryl, aryl(C₁-C₆)alkyl-, —O-aryl, CF₃, heterocycloalkyl,—(C₁-C₆)alkylheterocycloalkyl, —(C₂-C₇)alkenylheterocycloalkyl,heteroaryl, —(C₁-C₆)alkyl heteroaryl, —(C₂-C₇)alkenylheteroaryl,—(C₂-C₇)alkenylaryl, —(C₂-C₇)alkenylCOaryl, —(C₁-C₆)alkylN(R⁴)CO-aryl,—(C₁-C₆)alkylCO-aryl, —(C₁-C₆)alkylhydroxyaryl, —(C₁-C₆)alkyl-X-aryl,(C₂-C₇)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, ortetrahydronaphthalenyl, wherein X is O, S, SO, SO₂ or NR¹;—N(R¹)OCOaryl; ═CHCO₂R¹; ═CHCONR¹R²; ═CHCN; ═NNHSO₂R⁶ wherein R⁶ isaryl; —N(O)═CHR⁶; —OC(O)NR¹R⁷ wherein R⁷ is aryl, aryl(C₁-C₆)alkyl-,—(C₁-C₆)alkylCO₂(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl, —CO₂aryl, or—CO₂(C₁-C₆)alkylaryl; amino(C₁-C₆)alkylarylCO₂—; or —OC(O)OR⁸ wherein R⁸is (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl;

[0020] with the proviso that the cycloalkenyl ring is not aromatic.

[0021] In a preferred embodiment, R is substituted by —N(R¹)CONR²R³.

[0022] In a further preferred embodiment, R is substituted by—N(R⁴)COR⁵.

[0023] In a further preferred embodiment, R is substituted by—N(R¹)OCOaryl.

[0024] In a further preferred embodiment, R is substituted by ═CHCO₂Ry.

[0025] In a further preferred embodiment, R is substituted by═CHCONR¹R².

[0026] In a further preferred embodiment, R is substituted by ═CHCN.

[0027] In a further preferred embodiment, R is substituted by ═NNHSO₂R⁶.

[0028] In a further preferred embodiment, R is substituted by—N(O)═CHR⁶.

[0029] In a further preferred embodiment, R is substituted by—OC(O)NR¹R⁷.

[0030] In a further preferred embodiment, R is substituted byamino(C₁-C₆)alkylarylCO₂—.

[0031] In a further preferred embodiment, R is substituted by —OC(O)OR⁸.

[0032] The invention further provides a compound of formula I wherein Ris a (C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by ═CH₂,or a pharmaceutically acceptable salt thereof; with the proviso that thecycloalkenyl ring is not aromatic.

[0033] In a preferred embodiment, R is a cycloalkyl ring, and preferablya cyclohexyl or cyclopentyl ring. Where R is a cyclohexyl orcyclohexenyl ring, the ring is preferably substituted at the 3- or4-position, and more preferably at the 4-position. Where R is acyclopentyl or cyclopentenyl ring, the ring is preferably substituted atthe 3-position.

[0034] The invention further provides a compound of formula I wherein Ris 3-cyclohexenyl, which is preferably unsubstituted, or apharmaceutically acceptable salt thereof.

[0035] The invention further provides a compound of formula I, wherein Ris a (C₃-CB)cycloalkyl or (C₅-C₈)cycloalkenyl ring, wherein one of thecarbon atoms of said cycloalkyl or cycloalkenyl rings is substituted bytwo groups such that the said groups are taken together with the carbonto which they are attached to form a ring of the formula:

[0036] wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as definedabove; Z is CH₂, O, S, SO or SO₂; m is 0-3; with the proviso that whenm=0, then Z is CH₂; and with the proviso that the cycloalkenyl ring isnot aromatic; or a pharmaceutically acceptable salt thereof. In apreferred embodiment, m is 0. In a further preferred embodiment, m is 2.In a preferred embodiment, X and Z are both 0. In a further preferredembodiment, X and Z are both S. In a preferred embodiment, where R is acyclohexyl or cyclohexenyl ring, the carbon of the cyclohexyl orcyclohexenyl ring which is substituted by the two groups is at the 3- or4-position, and preferably at the 4-position, of the cyclohexyl orcyclohexenyl ring. In a further preferred embodiment, where R is acyclopentyl or cyclopentenyl ring, the carbon of the cyclopentyl orcyclopentenyl ring which is substituted by the two groups is at the3-position of the cyclopentyl or cyclopentenyl ring.

[0037] The invention further provides a compound of formula I, wherein Ris a (C₃-C₈)cycloalkyl or (C₁-C₈)cycloalkenyl ring, wherein one of thecarbon atoms of said cycloalkyl or cycloalkenyl rings is substituted bytwo groups such that the said groups are taken together with the carbonto which they are attached to form a ring of the formula:

[0038] wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as definedabove; and m is 0-3; and with the proviso that the cycloalkenyl ring isnot aromatic; or a pharmaceutically acceptable salt thereof. In apreferred embodiment, m is 2. In a further preferred embodiment, X is 0.In a preferred embodiment, where R is a cyclohexyl or cyclohexenyl ring,the carbon of the cyclohexyl or cyclohexenyl ring which is substitutedby the two groups is at the 3- or 4-position, and preferably at the4-position, of the cyclohexyl or cyclohexenyl ring. In a furtherpreferred embodiment, where R is a cyclopentyl or cyclopentenyl ring,the carbon of the cyclopentyl or cyclopentenyl ring which is substitutedby the two groups is at the 3-position of the cyclopentyl orcyclopentenyl ring.

[0039] The invention further provides a compound selected from the groupconsisting of:

[0040] 4-(1,4-Dioxaspiro[4.5]decyl)-1,3-benzenediol;

[0041] (±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;

[0042] (±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;

[0043] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0044] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;

[0045]trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;

[0046] trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0047] syn-8-(2,4-Dihydroxypheny)-1-oxaspiro[4.5]decan-2-one;

[0048] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea;

[0049] trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;

[0050] cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea;

[0051] cis-N-Benzyl-N[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;

[0052] trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;

[0053]trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;

[0054] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;

[0055] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;

[0056]trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;

[0057] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;

[0058] cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;

[0059] 4-(4-Methylenecyclohexyl)-1,3-benzenediol;

[0060] 4-(3-Cyclohexen-1-yl)-1,3-benzenediol;

[0061] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl(2R)-2-amino-3-phenylpropanoate;

[0062] Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;

[0063] 4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;

[0064]N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]4-methylbenzenesulfonohydrazide;

[0065] trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;

[0066] trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-phenylurea;

[0067] trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;

[0068]cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0069] cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy(trifluoromethyl)benzamide;

[0070]cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxymethoxybenzamide;

[0071] (±)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene] acetate;

[0072] and a pharmaceutically acceptable salt thereof.

[0073] The present invention further provides a pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing effective amount of a compoundof formula I:

[0074] or a pharmaceutically acceptable salt thereof, wherein:

[0075] R is a (C₃-C₈)cycloalkyl or (C₅-Cs)cycloalkenyl ring substitutedby —N(R¹)CONR²R³ wherein R¹ and R² are independently selected fromhydrogen, (C₁-C₆)alkyl, and aryl(C₁-C₆)alkyl and R³ is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; —N(R⁴)COR⁵ wherein R⁴ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-, or OH and R⁵ is(C₇-C₁₀)alkyl, aryl, aryl(C₁-C₆)alkyl-, —O-aryl, CF₃, heterocycloalkyl,—(C₁-C₆)alkylheterocycloalkyl, —(C₂-C₇)alkenylheterocycloalkyl,heteroaryl, —(C₁-C₆)alkyl heteroaryl, —(C₂-C,)alkenylheteroaryl,—(C₂-C₇)alkenylaryl, —(C₂-C₇)alkenylCOaryl, —(C₁-C₆)alkylN(R⁴)CO-aryl,—(C₁-C₆)alkylCO-aryl, —(C₁-C₆)alkylhydroxyaryl, —(C₁-C₆)alkyl-X-aryl,(C₂-C₇)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, ortetrahydronaphthalenyl, wherein X is O, S, SO, SO₂ or NR¹;—N(R¹)OCOaryl; ═CHCO₂R¹; ═CHCONR¹R²; ═CHCN; ═NNHSO₂R⁶ wherein R⁶ isaryl; —N(O)═CHR⁶; —OC(O)NR¹R⁷ wherein R⁷ is aryl, aryl(C₁-C₆)alkyl-,—(C₁-C₆)alkylCO₂(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl, —CO₂aryl, or—CO₂(C₁-C₅)alkylaryl; amino(C₁-C₅)alkylarylCO₂—; or —OC(O)OR⁸ wherein R¹is (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl;

[0076] with the proviso that the cycloalkenyl ring is not aromatic.

[0077] In a preferred embodiment, R is substituted by —N(R¹)CONR²R³.

[0078] In a further preferred embodiment, R is substituted by—N(R⁴)COR⁵.

[0079] In a further preferred embodiment, R is substituted by—N(R¹)OCOaryl.

[0080] In a further preferred embodiment, R is substituted by ═CHCO₂R¹.

[0081] In a further preferred embodiment, R is substituted by═CHCONR¹R².

[0082] In a further preferred embodiment, R is substituted by ═CHCN.

[0083] In a further preferred embodiment, R is substituted by ═NNHSO₂R⁶.

[0084] In a further preferred embodiment, R is substituted by—N(O)═CHR⁶.

[0085] In a further preferred embodiment, R is substituted by —OC(O)NRR⁷.

[0086] In a further preferred embodiment, R is substituted byamino(C₁-C₆)alkylarylCO₂—.

[0087] In a further preferred embodiment, R is substituted by —OC(O)OR⁸.

[0088] The invention further provides a pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula Iwherein R is a (C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substitutedby ═CH₂, with the proviso that the cycloalkenyl ring is not aromatic, ora pharmaceutically acceptable salt thereof.

[0089] In a preferred embodiment, R is a cycloalkyl ring, and preferablya cyclohexyl or cyclopentyl ring. Where R is a cyclohexyl orcyclohexenyl ring, the ring is preferably substituted at the 3- or4-position, and more preferably at the 4-position. Where R is acyclopentyl or cyclopentenyl ring, the ring is preferably substituted atthe 3-position.

[0090] The invention further provides a pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula Iwherein R is 3-cyclohexenyl, which is preferably unsubstituted, or apharmaceutically acceptable salt thereof.

[0091] The invention further provides a pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula I,wherein R is a (C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring, whereinone of the carbon atoms of said cycloalkyl or cycloalkenyl rings issubstituted by two groups such that the said groups are taken togetherwith the carbon to which they are attached to form a ring of theformula:

[0092] wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as definedabove; Z is CH₂, O, S, SO or SO₂; m is 0-3; with the proviso that whenm=0, then Z is CH₂; and with the proviso that the cycloalkenyl ring isnot aromatic; or a pharmaceutically acceptable salt thereof. In apreferred embodiment, m is 0. In a further preferred embodiment, m is 2.In a preferred embodiment, X and Z are both O. In a further preferredembodiment, X and Z are both S.

[0093] The invention further provides a pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula I,wherein R is a (C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring, whereinone of the carbon atoms of said cycloalkyl or cycloalkenyl rings issubstituted by two groups such that the said groups are taken togetherwith the carbon to which they are attached to form a ring of theformula:

[0094] wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as definedabove; and m is 0-3; and with the proviso that the cycloalkenyl ring isnot aromatic; or a pharmaceutically acceptable salt thereof. In apreferred embodiment, m is 2. In a further preferred embodiment, X is O.

[0095] In a preferred embodiment, the pharmaceutical composition of thepresent invention is adapted for topical application.

[0096] The invention further provides a pharmaceutical compositioncomprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound selected fromthe group consisting of:

[0097] 4-(1,4-Dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol;

[0098] (±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;

[0099] (±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;

[0100] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0101] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;

[0102]trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;

[0103] trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0104] syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;

[0105] cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea;

[0106] trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;

[0107] cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea;

[0108] cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;

[0109] trans-4=(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;

[0110]trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;

[0111] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;

[0112] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;

[0113]trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;

[0114] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;

[0115] cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;

[0116] 4-(4-Methylenecyclohexyl)-1,3-benzenediol;

[0117] 4-(3-Cyclohexen-1-yl)-1,3-benzenediol;

[0118] trans-4-(2,4-Dihydroxyphenyl)cyclohexyl(2R)-2-amino-3-phenylpropanoate;

[0119] Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;

[0120] 4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;

[0121]N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide;

[0122] trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;

[0123] trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-NV-phenylurea;

[0124] trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;

[0125]cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;

[0126]cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide;

[0127]cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-methoxybenzamide;

[0128] (±)-Methyl [4-(2,4-dihydroxyphenyl)cyclohexylidene] acetate;

[0129] and a pharmaceutically acceptable salt thereof.

[0130] The invention further provides a cosmetic composition comprisinga cosmetically acceptable topical carrier in combination with any one ormore of the compounds of formula I, or a cosmetically acceptable saltthereof.

[0131] The present invention further provides a method of lighteningskin in a human, comprising administering to said human askin-lightening or pigmentation-reducing effective amount of a compoundof formula I, or a pharmaceutically acceptable salt thereof. In apreferred embodiment, the present invention provides a method oflightening skin in a human in need of said treatment, comprisingadministering to said human a skin-lightening effective amount of acompound of formula I, or a pharmaceutically acceptable salt thereof.

[0132] The present invention further provides a method of inhibitingtyrosinase in a human, comprising administering to said human atyrosinase-inhibiting effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof. In a preferred embodiment, thepresent invention provides a method of inhibiting tyrosinase in a humanin need of said treatment, comprising administering to said human atyrosinase-inhibiting effective amount of a compound of formula I, or apharmaceutically acceptable salt thereof.

[0133] The present invention further provides a topical or transdermalpharmaceutical composition for the treatment of an inflammatory disorderor condition such as psoriasis, dermatitis or acne, or for the treatmentof dandruff, in a human in need of said treatment, comprising apharmaceutically acceptable carrier, and an amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, which amountis effective in treating such disorder or condition.

[0134] The present invention further provides a method of treating aninflammatory disorder, such as psoriasis, dermatitis or acne, or amethod of treating dandruff, in a human in need of said treatment,comprising administering to said human an amount of a compound offormula I, or a pharmaceutically acceptable salt thereof, which amountis effective in treating such disorder or condition.

[0135] The present invention further provides a kit, comprising acontainer comprising one or more specific compounds or pharmaceuticallyacceptable salts thereof, or pharmaceutical compositions, of the presentinvention that lighten skin. The kit may further comprise printedinstructions as a label or package insert directing the use of theenclosed compound or composition to lighten skin pigmentation.

[0136] As used herein, the terms “treat” and “treating”, and the like,refer to reversing, alleviating, inhibiting the progress of, orpreventing the disorder or condition to which such term applies, or oneor more symptoms of such disorder or condition. The term “treatment”, asused herein, refers to the act of treating, as “treating” is definedimmediately above.

[0137] The term “alkyl”, as used herein, unless otherwise indicated,includes saturated monovalent hydrocarbon radicals having straight,branched or cyclic moieties or combinations thereof. Any substituents orfunctional groups on the alkyl group, as indicated herein, can besubstituted anywhere on the alkyl group.

[0138] The term “alkenyl”, as used herein, unless otherwise indicated,includes unsaturated hydrocarbon radicals having straight, branched orcyclic moieties or combinations thereof, with one or more, andpreferably one or two, double bonds. Any substituents or functionalgroups on the alkyl group, as indicated herein, can be substitutedanywhere on the alkenyl group.

[0139] The term “aryl”, as used herein, refers to a (C₅-C₁₀) aryl,preferably phenyl or naphthyl, optionally substituted with one or moresubstituents, and preferably one or two substituents, independentlyselected from halogen, OH, (C₁-C₆)alkyl, amino, (C₁-C₆)alkylamino-,di-((C₁-C₆)alkyl))amino-, —NR¹COR¹ wherein each R¹ is independentlyselected from the group described above, nitro, cyano, —X—(C₁-C₆)alkyl,—X—(C₁-C₆)alkylaryl, —X— aryl, where X is defined above,trifluoromethyl, —OCF₃, —CO(C₁-C₆)alkyl, —COaryl, —COCF₃, —CONR₁₂,(C₂-C₇)alkenyl, aryl, (C₃-C₉)heterocycloalkyl, and (C₅-C₁₀)heteroaryl.Any substituents or functional groups on the aryl group, as indicatedherein, can be substituted anywhere on the aryl group.

[0140] The term “one or more substituents”, as used herein, refers to anumber of substituents that equals from one to the maximum number ofsubstituents possible based on the number of available bonding sites.

[0141] The term “halogen” as used herein, unless otherwise indicated,refers to chlorine, fluorine, bromine and iodine.

[0142] The term “heteroaryl”, as used herein, refers to a(C₂-C₁₀)heteroaryl, more preferably a (C₅-C₁₀)heteroaryl, and morepreferably a 5- or 6-membered heteroaryl, containing one to five N, O orS atoms. In a preferred embodiment, the heteroaryl is selected fromfuryl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl,isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, pyridyl, pyrimidinyl, pyrazinyl, pyridazinyl, triazinyl,pyrazolo[3,4-b]pyridinyl, pyrazolo[1,5-a]pyrimidinyl, cinnolinyl,pteridinyl, purinyl, benzo[b]thiophenyl,5,6,7,8-tetrahydro-quinolin-3-yl, 6,7-dihydro-5H-[1]pyridinyl,benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl,benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl,isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl,isoquinolinyl, quinolinyl, phthalazinyl, quinoxalinyl, quinazolinyl,benzoxazinyl, 4-oxo-1,4-dihydro[1,8]naphthyridin-3-yl,benzo[1,3]dioxol-5-yl, and 4-oxo-6,7-dihydro-5H-benzofuryl. One ofordinary skill in the art will understand that the connection of said(C₂-C₉)heteroaryl ring can be through a carbon atom or through anitrogen heteroatom where possible.

[0143] The heteroaryl may be optionally substituted with one or moresubstituents, preferably one or two substituents, independently selectedfrom halogen, OH, (C₁-C₆)alkyl, —(C₁-C₆)alkoxy, amino,(C₁-C₆)alkylamino-, di-((C₁-C₆)alkyl))amino-, —NR¹COR¹ wherein each R¹is independently selected from the group described above, nitro, cyano,—X—(C₁-C₆)alkyl, —X-aryl, where X is defined above, trifluoromethyl,—OCF₃, —S(O)_(p)(C₁-C₆)alkyl where p is 0, 1 or 2, —COaryl, —COCF₃,—CO(C₁-C₆)alkyl, —(C₁-C₆)alkylOH, —COOR¹, —(C₁-C₆)alkylCOOR¹, —CONR¹ ₂,(C₂-C₇)alkenyl, —CONH(CHR¹)_(q)CO₂R¹ where q is 1 or 2, —CONR¹N(R¹)₂,aryl, —(C₁-C₆)alkylaryl, (C₃-C₉)heterocycloalkyl, (C₅-C₁₀)heteroaryl,and —(C₁-C₆)alkyl(C₂-C₉)heteroaryl. Any substituents or functionalgroups on the heteroaryl group, as indicated herein, can be substitutedanywhere on the heteroaryl group.

[0144] The term “heterocycloalkyl”, as used herein, refers to a(C₂-C₁₀)heterocycloalkyl, more preferably a (C₅-C₁₀)heterocycloalkyl,and more preferably a 5- or 6-membered heterocycloalkyl, containing fromone to five N, O or S atoms. In a preferred embodiment, theheterocycloalkyl group is selected from pyrrolidinyl,dihydropyrrolindinyl, tetrahydrofuranyl, dihydrofuranyl,tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl,methylenedioxyl, chromenyl, isoxazolidinyl, oxazolidinyl,isothiazolidinyl, thiazolidinyl, pyrazolidinyl, piperidinyl,thiomorpholinyl, tetrahydrothiazinyl, thiadiazinyl,-tetrahydrothiadiazinyl, morpholinyl, tetrahydrodiazinyl,tetrahydroazepinyl, piperazinyl, chromanyl, oxopyrrolidinyl,1,3-dioxo-1,3-dihydroisoindolyl,6-oxo-1,4,5,6,-tetrahydropyridazin-4-yl,2,3-dihydrobenzo[1,4]dioxin-2-yl, 2-oxo-2H-chromen-5-yl,benzo[1,3]dioxol-5-yl, and 3-oxo-3H-isobenzofuran-1-ylidinemethyl. Oneof ordinary skill in the art will understand that the connection of saidheterocycloalkyl ring can be through a carbon atom or through a nitrogenheteroatom where possible.

[0145] The heterocycloalkyl may be optionally substituted with one ormore substituents, preferably one or two substituents, independentlyselected from halogen, OH, —(C₁-C₆)alkyl, —(C₁-C₆)alkoxy,—S(O)P(C₁-C₆)alkyl where p is 0, 1 or 2, amino, ═O, (C₁-C₆)alkylamino,di-((C₁-C₆)alkyl))amino, NR¹COR¹ wherein each R¹ is independentlyselected from the group described above, —COOR¹, —(C₁-C₆)alkylCOOR¹,—CONH(CHR¹)_(q)CO₂R¹ where q is 1 or 2, —CONR¹N(R¹)₂, —(C₁-C₆)alkylOH,—CO(C₁-C₆)alkyl, nitro, cyano, —X—(C₁-C₆)alkyl, —X-aryl, where X isdefined above, trifluoromethyl, —OCF₃, —COaryl, —COCF₃, —CO(C₁-C₆)alkyl,—CONR¹ ₂, (C₂-C₇)alkenyl, (C₁-C₆)alkylaryl, aryl,(C₃-C₉)heterocycloalkyl, (C₅-C₁₀)heteroaryl; and —CO₂(C₁-C₆)alkyl. Anysubstituents or functional groups on the aryl group, as indicatedherein, can be substituted anywhere on the aryl group. In a preferredembodiment, the heterocycloalkyl group is substituted with one or moresubstituents, preferably one or two substituents, independently selectedfrom halogen, OH, —(C₁-C₆)alkyl, amino, and trifluoromethyl. Anysubstituents or functional groups on the heterocycloalkyl group, asindicated herein, can be substituted anywhere on the aryl group.

[0146] Compounds of formula I may contain chiral centers and thereforemay exist in different enantiomeric and diastereomeric forms. Thisinvention relates to all optical isomers, stereoisomers and tautomers ofthe compounds of formula I, II and III, and mixtures thereof, and to allpharmaceutical compositions and methods of treatment defined above thatcontain or employ them, respectively.

[0147] Formula I, as defined above, also includes compounds identical tothose depicted but for the fact that one or more hydrogen, carbon orother atoms are replaced by isotopes thereof. Such compounds may beuseful as research and diagnostic tools in metabolism pharmacokineticstudies and in binding assays.

[0148] The present invention also relates to the pharmaceuticallyacceptable acid addition and base salts of any of the aforementionedcompounds of formula I. The acids that are used to prepare thepharmaceutically acceptable acid addition salts of the aforementionedbase compounds of this invention are those that form non-toxic acidaddition salts, i.e., salts containing pharmacologically acceptableanions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate,sulfate, bisulfate, phosphate, acetate, lactate, citrate, tartrate,bitartrate, succinate, maleate, fumarate, gluconate, saccharate,benzoate, methanesulfonate, ethanesulfonate, benzenesulfonatep-toluenesulfonate and pamoate (i.e.,1,1-methylene-bis-(2-hydroxy-3-naphthoate)) salts.

[0149] As used herein, a “skin-lightening or pigmentation reducingamount of a compound of formula I”, and the like, means an amount orconcentration of the compound capable of detectably lightening skin orreducing pigmentation in a human, as determined by any standard assay.The active compound is typically administered in a pharmaceuticalcomposition and for a standard course of treatment that produces thedesired result of skin depigmentation.

[0150] As used herein, a “tyrosinase-inhibiting effective amount of acompound of formula I”, and the like, means an amount or concentrationof the compound capable of detectably inhibiting tyrosinase activity ina human, as determined by any standard assay, such as those describedbelow.

[0151] As used herein, an “amount of a compound of formula I capable oftreating an inflammatory disorder such as psoriasis, dermatitis or acne,or treating dandruff”, and the like, means an amount or concentration ofthe compound capable of detectably ameliorating, reducing, eliminating,slowing, or preventing the progression of, any symptom or conditionassociated with or caused by such disorder or condition, in a human, asdetermined by any standard assay.

DETAILED DESCRIPTION OF THE INVENTION

[0152] The compounds of formula I may be prepared as described in thefollowing reaction schemes and discussion. Unless otherwise indicated m,R⁶, X, Z and structural formula I in the reaction schemes and discussionthat follow are as defined above, and n=0-5.

[0153] Y, Y^(I), Y^(II) shown in the schemes above each independentlyrepresents any of the components of the various substituents on R asdefined above, or hydrogen as appropriate.

[0154] Referring to Scheme 1, compounds of formula (2) can be preparedstarting with compound (1), which is commercially available (Aldrich,Milwaukee, Wis., USA). Conversion into compounds of formula (2) canoccur under standard conditions, for example, where the protecting groupis benzyl, condensation can occur between compound (1) and benzylalcohol with the removal of water using a Dean-Stark apparatus inconjunction with well-known methodology. Condensation of compounds offormula (2) with compounds of formula (3) can occur using standardtechniques, for example, treatment of compounds of formula (2) with abase such as lithium diisopropylamide in an ethereal solvent followed bythe addition of a compound of formula (3) at low temperature would givecompounds of formula (4). Compound (3) where n=3 is commerciallyavailable (Aldrich, Milwaukee, Wis., USA). Treatment of compounds offormula (4) with a suitable halogenating reagent such asN-bromosuccinimide in a chlorinated solvent at about room temperaturecan give compounds of formula (5). Compounds of formula (6) can then begenerated from compounds of formula (5) under suitable conditions. Suchconditions can involve treating compounds of formula (5) with a basesuch as 1,8-diazobicyclo[5.4.0]undec-7-ene in a suitable solvent such asN,N-dimethylformamide at about 140° C. Treatment of compounds of formula(6) to standard hydrogenation conditions, e.g., hydrogen gas andpalladium on charcoal in ethanol, yields compounds of the generalformula 1 (7) when the protecting group is benzyl. Compounds of formula(8) can then be obtained by treating compounds of formula (7) to acidicconditions.

[0155] Conversion of compounds of formula (8) into compounds of formulaI may involve the need to use protecting groups that will be obvious tothose of skill in the art. Compounds of formula (9), where PG is asuitable protecting group, can be manipulated through several steps togive compounds of formula I where R is substituted with an amide, urea,hydroxylamine or hydroxamic acid. An example of a suitable protectinggroup is tert-butyldimethylsilyl. Treatment of compounds of formula (8)with tert-butyldimethylsilyl chloride in a suitable solvent, e.g., DMF,in the presence of a suitable base such as imidazole, at about roomtemperature, will give compounds of formula (9). Treatment of compoundsof formula (9) with benzylamine under reductive amination conditions,e.g., sodium triacetoxyborohydride in a suitable solvent, e.g.,dichloroethane, will give compounds of formula (10). For compounds offormula I where Y^(I)=H, hydrogenolysis under standard conditions, e.g.,palladium on charcoal, hydrogen gas, ethanol, followed by amide bondformation, e.g., using an acid chloride in the presence of a suitablebase such as triethylamine, provides compounds of formula I aftersuitable deprotection. When PG is tert-butyldimethylsilyl, suitabledeprotection may involve the use of tetrabutylammonium fluoride in asuitable solvent such as THF, at about room temperature. Alternatively,amides can be prepared from compounds of formula (10) using an acid anda suitable coupling reagent, which are well known to those with skill inthe art. One such suitable coupling reagent isO-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate used in the presence of a base such asdiisopropylamine at about room temperature. Compounds where R issubstituted with a urea may be formed from compounds of formula (10)using standard conditions, e.g., an isocyanate and a base such asdiisopropylamine in DCM at about 40° C. Compounds where R is substitutedwith a hydroxylamine or hydroxamic acid, can be synthesised fromcompounds of formula (10) by treatment with benzoylperoxide in asuitable solvent such as DCM, at about room temperature, to givecompounds of formula (11). Treatment of compounds of formula (11), whereY^(I)=H, with an acid chloride in the presence of a base, such astriethylamine, in a chlorinated solvent, after suitable deprotection andtreatment with a base such as 2M NaOH at about room temperature, wouldgive compounds of formula I where R is substituted with a hydroxamicacid. Treatment of compounds of formula (11) to suitable deprotectionfollowed by treatment with a base such as 2M NaOH at about roomtemperature, would give compounds of formula I where R is substitutedwith a hydroxylamine.

[0156] Referring to scheme 2, compounds of formula (9) can bederivatised to yield compounds of formula I (13) using standard Wittigor Wadworths-Emmons chemistry known to those of skill in the art. Forexample, when Y=CN, treating diethylcyanomethyl-phosphonate with asuitable base, e.g., sodium hydride, in a suitable solvent, e.g.,dimethoxyethane, followed by a compound of formula (9), would give,after suitable deprotection, compounds of formula 1 (13). Compounds offormula (9) may also be reduced under standard conditions, e.g., sodiumborohydride in ethanol at about room temperature, to give compounds offormula (12). Compounds of formula (12) may then be further derivatisedto give compounds of formula I where Y is an amino acid usingconventional coupling methods. Such methods may involve the use of anacid chloride, and base such as triethylamine in a suitable solvent suchas dichloromethane. Treatment of compounds of formula (12) with sodiumhydride and a suitable chloroformate reagent would give compounds offormula I where R is substituted with a carbonate. Treatment ofcompounds of formula (12) with an isocyanate and base, e.g.,diisoproylamine, in a suitable solvent, e.g., DMF, at about 50° C.,after deprotection, would give compounds of formula I where R issubstituted with a carbamate. Compounds of formula I whereR=cyclohexenyl may be produced from compounds of formula (12) underdehydrating conditions. Such conditions may involve treating a compoundof formula (12) with (diethylamino)sulfur trifluoride in a solvent suchas DCM, at about room temperature.

[0157] Compounds of formula I (14), where X=O and m=2, may be preparedfrom compounds of formula (9). Treatment of compounds of formula (14)with samarium diiodide and ethylacrylate in a suitable solvent such asTHF gives, after suitable deprotection, compounds of formula 1 (14).Where R is substituted with ═NNHSO₂R⁶, heating compounds of formula (9)with the appropriate sulfonyl hydrazide in a solvent such as ethanolgives, after suitable deprotection, compounds of formula 1. Compounds offormula I (15) may be synthesised from compounds of formula (9) understandard conditions, for example, where X and Z are S, and m is 2,treating compounds of formula (9) with propanedithiol and an acid, e.g.,para-toluene sulfonic acid, under dehydrating conditions, followed bysuitable deprotection.

[0158] Referring to Scheme 3, compounds of formula (17) can be formed byprotecting commercially available 4-bromoresorcinol (16) (AldrichChemical Company). A suitable protecting group such as methoxymethyl(MOM) can be introduced by conventional methods that are well known tothose skilled in the art. For example, alkylation of 4-bromoresorcinolcan occur with two equivalents of methoxymethyl chloride in the presenceof diisopropylamine in a halogenated solvent at about 0° C. to roomtemperature. The compound of the formula (18) is commercially available(Aldrich Chemical Company). Compounds of formula (19) can be obtainedfrom the reaction of compounds of formula (17) with n-butyllithium inthe presence of N,N,N′,N′-tetramethylethylenediamine in an etherealsolvent, followed by the addition of a compound of formula (18).Dehydration of compounds of formula (19) under standard conditions,e.g., heating compounds of formula (19) at about 110° C. in a Dean-Starkapparatus in the presence of camphor sulfonic acid in a suitable solvent(e.g., toluene), yields compounds of formula (20). Hydrogenation understandard conditions, e.g., using hydrogen gas and palladium on charcoalin ethanol, yields compounds of the general formula (21) and hydrolysis,e.g., aqueous hydrochloric acid at about room temperature, yieldscompounds of formula (22).

[0159] It will be appreciated by those of skill in the art that in theprocesses described above, the functional groups of intermediatecompounds may need to be protected by protecting groups. The use ofprotecting groups is well-known in the art, and is fully described,among other places, in: Protecting Groups in Organic Chemistry, J. W. F.McOmie, (ed.), 1973, Plenum Press; and in: Protecting Groups in OrganicSynthesis, 2^(nd) edition, T. W. Greene & P. G. M. Wutz, 1991,Wiley-Interscience, which are incorporated by reference in theirentirety.

[0160] The compounds of formula I that are basic in nature are capableof forming a wide variety of different salts with various inorganic andorganic acids. Although such salts must be pharmaceutically acceptablefor administration to animals, it is often desirable in practice toinitially isolate a compound of formula I from the reaction mixture as apharmaceutically unacceptable salt and then simply convert the latterback to the free base compound by treatment with an alkaline reagent andsubsequently convert the latter free base to a pharmaceuticallyacceptable acid addition salt. The acid addition salts of the activebase compounds of this invention are readily prepared by treating thebase compound with a substantially equivalent amount of the chosenmineral or organic acid in an aqueous solvent medium or in a suitableorganic solvent, such as methanol or ethanol. Upon careful evaporationof the solvent, the desired solid salt is readily obtained.

[0161] Those compounds of formula I that are acidic in nature arecapable of forming base salts with various pharmaceutically acceptablecations. Examples of such salts include the alkali metal and alkalineearth metal salts and, particularly, the sodium and potassium salts.These salts can be prepared by conventional techniques. The chemicalbases that are used as reagents to prepare the pharmaceuticallyacceptable base salts of this invention are those that form non-toxicbase salts with the acidic compounds of formula I. Such non-toxic basesalts include those derived from such pharmaceutically acceptablecations as sodium, potassium, calcium and magnesium, etc. These saltscan easily be prepared by treating the corresponding acidic compoundswith an aqueous solution containing the desired pharmaceuticallyacceptable cations, and then evaporating the resulting solution todryness, preferably under reduced pressure. Alternatively, they can alsobe prepared by mixing lower alkanolic solutions of the acidic compoundsand the desired alkali metal alkoxide together, and then evaporating theresulting solution to dryness, as described above. In either case,stoichiometric quantities of reagents are preferably employed in orderto ensure completeness of reaction and maximum yields of the desiredfinal products.

[0162] Compounds of formula I and their pharmaceutically acceptablesalts (hereinafter “the active compounds used in this invention”) areuseful in the treatment of disorders of human pigmentation, includingsolar and simple lentigines (including age/liver spots),melasma/chloasma and postinflammatory hyperpigmentation. The activecompounds used in this invention reduce skin melanin levels byinhibiting the production of melanin, whether the latter is producedconstitutively or in response to UV irradiation (such as sun exposure).Thus, the active compounds used in this invention can be used to reduceskin melanin content in non-pathological states so as to induce alighter skin tone, as desired by the user, or to prevent melaninaccumulation in skin that has been exposed to UV irradiation. Thus, theactive compounds used in this invention can be used simply to lightenskin where no pathological or disease condition exists. The activecompounds used in this invention can also be used for cosmetic purposes.As used herein to refer to the depigmentation aspect of the invention,the term “a human in need of said treatment” refers to a human who, forany reason, whether medical or cosmetic, desires to reduce the melanincontent of their skin or to prevent the melanization of their skin onany portion of their body.

[0163] The compounds of this invention can be prepared as cosmetics,quasi-drugs (where applicable), or pharmaceutical drugs. As cosmetics,the compounds of the present invention are useful in improving overallskin tone and texture.

[0164] The compounds of this invention can appropriately be combinedwith other components. Examples of such components include oilycomponents such as hydrocarbons, fats and oils such as liquid paraffin,squalene, vaseline, cetyl alcohol, isostearyl alcohol,cetyl-2-ethylhexanoate, 2-octyldodecyl alcohol, glycerin triiostearate,nut oils, and lanolin, as well as wax, silicone, surfactants,thickeners, neutralizers, antiseptics, germicides, anti-oxidants, powdercomponents, pigments, perfumes, ultraviolet light absorbents, drugs,metallic sealant, and pH modifiers. Thus, cosmetics, quasi-drugs (whereapplicable), and pharmaceutical drugs of the present invention can beprepared using dermatologically, cosmetically or pharmaceuticallyacceptable carriers as appropriate, and as known in the art.

[0165] Occurrences in the skin or hair of noticeable but undesiredpigmentation as a result of melanin production, overproduction orunderproduction can be treated using the methods of the presentinvention. Cosmetic applications for methods of the present inventioninclude the topical application of compositions containing one or moreof the compounds of the present invention to enhance or otherwise alterthe visual appearance of skin or hair. The cosmetic compositions of thepresent invention are also useful to provide a smoother or softer skinappearance or texture.

[0166] The active compounds used in this invention can also be used incombination with skin peeling agents (including glycolic acid ortrichloroacetic acid face peels) to lighten skin tone and preventrepigmentation. The appropriate dose regimen, the amount of each doseadministered, and specific intervals between doses of the activecompound will depend upon the particular active compound employed, thecondition of the patient being treated, and the nature and severity ofthe disorder or condition being treated. Preferably, the active compoundis administered in an amount and at an interval that results in thedesired treatment of or improvement in the disorder or condition beingtreated.

[0167] An active compound used in this invention can also be used incombination with sun screens (UVA or UVB blockers) to preventrepigmentation, to protect against sun or UV-induced skin darkening orto enhance their ability to reduce skin melanin and their skin bleachingaction. An active compound used in this invention can also be used incombination with retinoic acid or its derivatives or any compounds thatinteract with retinoic acid receptors and accelerate or enhance theinvention's ability to reduce skin melanin and skin bleaching action, orenhance the invention's ability to prevent the accumulation of skinmelanin. An active compound used in this invention can also be used incombination with 4-hydroxyanisole.

[0168] An active compound used in this invention can also be used incombination with ascorbic acid, its derivatives and ascorbic-acid basedproducts (such as magnesium ascorbate) or other products with ananti-oxidant mechanism (such as resveratrol) which accelerate or enhancetheir ability to reduce skin melanin and their skin bleaching action.

[0169] As one skilled in the art would know in view of this disclosure,an active compound used in the methods of the present invention may beused alone or in combination with other compounds known in the art toaffect melanin synthesis, particularly other melanin synthesisinhibitors, including tyrosinase inhibitors. Such inhibitors includethose currently known in the art and those to be developed in thefuture. Known inhibitors include various resorcinol derivatives, kojicacid derivatives, hydroquinone, melamine, and various types of plantextracts, among others. For example, any of the compounds used accordingto a skin-lightening method of the present invention may be used incombination with a tyrosinase inhibitor or other skin-whitening agent,including any one or more of those agents, including compounds orextracts, described in the following patent publications: U.S. Pat. No.4,278,656 to Nagai et al, issued Jul. 14, 1981, describing the use ofkojic acid and its derivatives; U.S. Pat. No. 4,369,174 to Nagai et al.,issued Jan. 18, 1983, describing the use of kojic acid and itsderivatives; U.S. Pat. No. 4,959,393 to Torihara et al., issued Sep. 25,1990, describing the use of 4-n-butylresorcinol, 4-isoamyl resorcinoland other resorcinol derivatives; U.S. Pat. No. 5,580,549 to Fukuda etal., issued Dec. 3, 1996, describing the use of various hydroxybenzoicacid derivatives; U.S. Pat. No. 6,123,959 to Jones et al., issued Sep.26, 2000, describing the use of liposomes containing combinations ofcompetitive inhibitors, such as arbutin, and non-competitive inhibitors,such as aloesin, of melanin synthesis; U.S. Pat. No. 6,132,740 to Hu,issued Oct. 17, 2000, describing the use of various resorcinolderivatives; U.S. Pat. No. 6,159,482 to Tuloup et al., issued Dec. 12,2000, describing the use of various hydroxyphenyl oxamate derivatives;WO 99/32077 by L'Oreal, published Jul. 1, 1999, describing the use ofvarious phenolic amides; WO 99/64025 by Fytokem Prod. Inc., publishedDec. 16, 1999, describing the use of various dicotyledonous plantextracts; WO 00/56702 by Pfizer Inc., published Sep. 28, 2000 describingvarious resorcinol derivatives; WO 00/76473 by Shiseido Co. Ltd.,published Dec. 12, 2000, describing the use of Withania plant extracts;EP 997140 by L'Oreal SA, published May 3, 2000, describing the use ofcombinations of mulberry and skullcap extracts with salicylic acidderivatives; JP 5221846 by Kunimasa Tomoji, published Aug. 31, 1993,describing the use of kojic acid derivatives; JP 7242687 by Shiseido Co.Ltd., published Sep. 19, 1995, describing the use of Trichodermaextracts; JP 7324023 by Itogawa H, published Dec. 12, 1995, describing,the use of Pseudostellariae radix extracts; JP 8012552 by Shiseido Co.Ltd., published Jan. 16, 1996, describing the use of Amor seco extracts;JP 8012554 by Shiseido Co. Ltd., published Jan. 16, 1996, describing theuse of Jabonciilo extracts; JP 8012557 by Shiseido Co. Ltd., publishedJan. 16, 1996, describing the use of Huaca extracts; JP 8012560 byShiseido Co. Ltd., published Jan. 16, 1996, describing the use ofCopaiba extracts; JP 8012561 by Shiseido Co. Ltd., published Jan. 16,1996, describing the use of Arnica extracts; JP 8134090 by Fujisawa,published May 28, 1996, describing the use of galactosyl-kojic acidderivatives; JP,8168378 by Kirinjo KK, published Jul. 2, 1996,describing the use of lees from rice wine production; JP 8277225 byKansai Koso KK, published Oct. 22, 1996, describing the use ofAutocarpus incisus extracts; JP 9002967 by Sanki Shoji KK, publishedJan. 7, 1997, describing the use of Prunus domesticus extracts; JP9295927 by Yagi Akira, published Nov. 18, 1997, describing the use ofAloe vera extracts; JP 10072330 by Kansai Kouso, published Mar. 17,1998, describing the use of oxydesberatrdl derivatives; JP 10081626 byKamiyama KK, published Mar. 31, 1998, describing the use of4-substituted benzoic acids; JP 10101543 by Kansai Kouso KK, publishedApr. 21, 1998, describing the use of flavonoids; JP 11071231 by MaruzenPharm., published Mar. 16, 1999, describing the use of bakuchiol; JP11079934 by Kyodo Nyugyo, published Mar. 23, 1999, describing the use oflow molecular weight thiol from sake lees; JP 11246347 by Shiseido Co.Ltd., published Sep. 14, 1999, describing the use of Achilleamillefolium extracts; JP 11246344 by Shiseido Co. Ltd., published Sep.14, 1999, describing the use of Gliricidia extracts; JP 2000-080023 byKanebo Ltd., published Mar. 21, 2000, describing the use ofmetallothionine inducers; JP 2000-095663 by Kose KK, published Apr. 4,2000, describing the use of various plant extracts; JP 2000-159681 byHai Tai Confectionary Co. Ltd., published Jun. 13, 2000, describing theuse of grape seed extract; JP-7206753 by Nikken Food KK, published Aug.8, 1995, describing the use of dihydroxycurcumin derivatives; JP-5320025by Kunimasa T, published Dec. 3, 1993, describing the use of kojic acidderivatives; and JP-59157009 by Yakurigaku Chuou K E, published Sep. 6,1984, describing the use of O-thujaplicin, hydroquinone or a pyronecompound in combination with a melanin adsorbent; among others; whichpatent publications are incorporated herein by reference in theirentireties.

[0170] This invention relates both to methods of lightening or reducingthe pigmentation of skin in which an active compound used in thisinvention, and one or more of the other active ingredients, such asthose referred to above, are administered together as part of the samepharmaceutical composition, as well as methods in which they areadministered separately as part of an appropriate dose regimen designedto obtain the benefits of the combination therapy. The appropriate doseregimen, the amount of each dose administered, and specific intervalsbetween doses of each active agent will depend upon the specificcombination of active agents employed, the condition of the patientbeing treated, and the nature and severity of the disorder or conditionbeing treated. Such additional active ingredients will generally beadministered in amounts less than or equal to those for which they areeffective as single topical therapeutic agents. The FDA approved dosagesfor such active agents that have received FDA approval foradministration to humans are publicly available.

[0171] An active compound of this invention will generally beadministered in the form of a pharmaceutical composition comprising atleast one compound of formula (I), together with a pharmaceuticallyacceptable vehicle or diluent. Alternatively, an active compound of thisinvention can be administered in the form of a cosmetic compositioncomprising at least one compound of formula (1), together with acosmetically acceptable vehicle or diluent. Such a composition isgenerally formulated in a conventional manner utilizing solid or liquidvehicles or diluents as appropriate for topical administration, in theform of solutions, gels, creams; jellies, pastes, lotions, ointments,salves, aerosols and the like.

[0172] Examples of vehicles for application of the active compounds ofthis invention include an aqueous or water-alcohol solution, an emulsionof the oil-in-water or water-in-oil type, an emulsified gel, or atwo-phase system. Preferably, the compositions according to theinvention are in the form of lotions, creams, milks, gels, masks,microspheres or nanospheres, or vesicular dispersions. In the case ofvesicular dispersions, the lipids of which the vesicles are made can beof the ionic or nonionic type, or a mixture thereof. Such vehicles caninclude suitable viscosity enhancing agents, pH adjusting agents,stabilizers, fragrances, etc., as known in the art of topicalformulations.

[0173] An effective dosage and treatment protocol can be determined byconventional means, starting with a low dose in laboratory animals andthen increasing the dosage while monitoring the effects, andsystematically varying the dosage regimen as well. Animal studies,preferably mammalian studies, are commonly used to determine the maximaltolerable dose, or MTD, of a bioactive agent per kilogram weight. Thoseskilled in the art can extrapolate doses for efficacy and avoidance oftoxicity to other species, including humans.

[0174] Before human studies of efficacy are undertaken, Phase I clinicalstudies in normal subjects can help establish safe doses. Numerousfactors can be taken into consideration by a clinician when determiningan optimal dosage for a given subject. Primary among these is thetoxicity and half-life of the chosen compound. Additional factorsinclude the size of the patient, the age of the patient, the generalcondition of the patient, the particular disease, condition, or disorderbeing treated, the severity of the disease, condition, or disorder beingtreated, the presence of other drugs in the patient, the effect desired,and the like. The trial dosages would be chosen after consideration ofthe results of animal studies and the clinical literature.

[0175] One of ordinary skill in the art will appreciate that theendpoint of treatment chosen in a particular case will vary according tothe disease, condition, or disorder being treated, the outcome desiredby the patient, subject, or treating physician, and other factors. Wherethe composition is being used to lighten skin color such as, forexample, to reverse hyperpigmentation caused by, for example,inflammation or diseases such as melasma, or to lighten hair color, anyone of a number of endpoints can be chosen. For example, endpoints canbe defined subjectively such as, for example, when the subject is simply“satisfied” with the results of the treatment. For pharmacologicalcompositions, the endpoint can be determined by the patient's, or thetreating physician's, satisfaction with the results of the treatmentAlternatively, endpoints can be defined objectively. For example, thepatient's or subject's skin or hair in the treated area can be comparedto a color chart. Treatment is terminated when the color of the skin orhair in the treated area is similar in appearance to a color on thechart. Alternatively, the reflectance of the treated skin or hair can bemeasured, and treatment can be terminated when the treated skin or hairattains a specified reflectance. Alternatively, the melanin content ofthe treated hair or skin can be measured. Treatment can be terminatedwhen the melanin content of the treated hair or skin reaches a specifiedvalue. Melanin content can be determined in any way known to the art,including by histological methods, with or without enhancement by stainsfor melanin.

[0176] In the depigmenting compositions according to the presentinvention, the concentration of the active compound of the invention isgenerally between 0.01 and 10%, preferably between 0.1 and 10%, relativeto the total weight of the composition.

[0177] The compositions of this invention can optionally also contain amoistener, a surfactant, keratolytic, an anti-inflammatory agent, acomplexing agent, an antioxidant, a preservative, a colorant, afragrance, or a sunscreen.

[0178] The compositions of the present invention can be applied directlyto the skin. Alternatively, they can be delivered by various transdermaldrug delivery systems, such as transdermal patches as known in the art.For example, for topical administration, the active ingredient can beformulated in a solution, gel, lotion, ointment, cream, suspension,paste, liniment, powder, tincture, aerosol, patch, or the like in apharmaceutically or cosmetically acceptable form by methods well knownin the art. The composition can be any of a variety of forms common inthe pharmaceutical or cosmetic arts for topical application to animalsor humans, including solutions, lotions, sprays, creams, ointments,salves, gels, etc., as described below. Preferred agents are those thatare viscous enough to remain on the treated area, those that do notreadily evaporate, and/or those that are easily removed by rinsing withwater, optionally with the aid of soaps, cleansers and/or shampoos.Actual methods for preparing topical formulations are known or apparentto those skilled in the art, and are described in detail in Remington'sPharmaceutical Sciences, 1990 (supra); and Pharmaceutical Dosage Formsand Drug Delivery Systems, 6th ed., Williams & Wilkins (1995).

[0179] In order to enhance the percutaneous absorption of the activeingredients, one or more of a number of agents can be added in thetopical formulations including, but not limited to, dimethylsulfoxide,dimethylacetamide, dimethylformamide, surfactants, azone, alcohol,acetone, propylene glycol and polyethylene glycol. In addition, physicalmethods can also be used to enhance transdermal penetration such as,e.g., by iontophoresis or sonophoresis. Alternatively, or in addition,liposomes may be employed.

[0180] A topically applied composition of the invention contains apharmaceutically effective agent that lightens skin as described herein,and those ingredients as are necessary for use as a carrier, such as anemulsion, a cream, an ointment, an aqueous solution, a lotion or anaerosol. Non-limiting examples of such carriers are described in moredetail below and may be found in International Patent Publication WO00/62742, published Oct. 26, 2000; U.S. Pat. No. 5,691,380 to Mason etal., issued Nov. 25, 1997; U.S. Pat. No. 5, 968,528 to Deckner et al.,issued Oct. 19, 1999; U.S. Pat. No. 4,139,619 to Chidsey, III, issuedFeb. 13, 1979; and U.S. Pat. No. 4,684,635 to Orentreich et al., issuedAug. 4, 1987; which are incorporated herein by reference. Suitablepharmaceutical carriers are further described in Remington'sPharmaceutical Sciences, 17th ed., Mack Publishing Company, Easton, Pa.(1990), which is a standard reference text in this field.

[0181] The pharmaceutical compositions of the invention may optionallyinclude components suitable for application to keratinous tissue, thatis, when incorporated into the composition, they are suitable for use incontact with human keratinous tissue without undue toxicity,incompatibility, instability, allergic response, and the like within thescope of sound medical judgment. In addition, such optional componentsare useful provided that they do not unacceptably alter the benefits ofthe active compounds of the invention. The CTFA Cosmetic IngredientHandbook, Second Edition (1992) describes a wide variety of non-limitingcosmetic and pharmaceutical ingredients commonly used in the skin careindustry, which are suitable for use in the compositions of the presentinvention. Examples of these ingredient classes include: abrasives,absorbents, aesthetic components such as fragrances, pigments,colorings/colorants, essential oils, skin sensates, astringents, etc.(e.g., clove oil, menthol, camphor, eucalyptus oil, eugenol, menthyllactate, witch hazel distillate), anti-acne agents, anti-caking agents,antifoaming agents, antimicrobial agents (e.g., iodopropylbutylcarbamate), antioxidants, binders, biological additives, bufferingagents, bulking agents, chelating agents, chemical additives, colorants,cosmetic astringents, cosmetic biocides, denaturants, drug astringents,external analgesics, film formers or materials, e.g., polymers, foraiding the film-forming properties and substantivity of the composition(e.g., copolymer of eicosene and vinyl pyrrolidone), opacifying agents,pH adjusters, propellants, reducing agents, sequestrants,skin-conditioning agents (e.g., humectants, including miscellaneous andocclusive), skin soothing and/or healing agents (e.g., panthenol andderivatives (e.g., ethyl panthenol), aloe vera, pantothenic acid and itsderivatives, allantoin and bisabolol and dipotassium glycyrrhizinate),skin treating agents, thickeners, and vitamins and derivatives thereof.

[0182] In addition to the pharmaceutically effective amount of an agentdisclosed herein, the topical compositions of the present invention alsocomprise a dermatologically acceptable carrier. The phrase“dermatologically acceptable carrier”, as used herein, means that thecarrier is suitable for topical application to the skin, i.e.,keratinous tissue, has good aesthetic properties, is compatible with theactive agents of the present invention and any other components, andwill not cause any safety or toxicity concerns. A safe and effectiveamount of carrier is from about 50% to about 99.99%, preferably fromabout 80% to about 99.9%, more preferably from about 90% to about 98%,and most preferably from about 90% to about 95% of the composition.

[0183] The carrier utilized in the compositions of the invention can bein a wide variety of forms. These include emulsion carriers, including,but not limited to, oil-in-water, water-in-oil, water-in-oil-in-water,and oil-in-water-in-silicone emulsions, a cream, an ointment, an aqueoussolution, a lotion or an aerosol. As will be understood by the skilledartisan, a given component will distribute primarily into either thewater or oil/silicone phase, depending on the watersolubility/dispersibility of the component in the composition.

[0184] Emulsions according to the present invention generally contain apharmaceutically effective amount of an agent disclosed herein and alipid or oil. Lipids and oils may be derived from animals, plants, orpetroleum and may be natural or synthetic (i.e., man-made). Preferredemulsions also contain a humectant, such as glycerin. Emulsions willpreferably further contain from about 1% to about 10%, more preferablyfrom about 2% to about 5%, of an emulsifier, based on the weight of thecarrier. Emulsifiers may be nonionic, anionic or cationic. Suitableemulsifiers are described in, for example, U.S. Pat. No. 3,755,560 toDickert et al., issued Aug. 28, 1973; U.S. Pat. No. 4,421,769 to Dixon,et al., issued Dec. 20, 1983; and McCutcheon's Detergents andEmulsifiers, North American Edition, pages 317-324 (1986).

[0185] The emulsion may also contain an anti-foaming agent to minimizefoaming upon application to the keratinous tissue. Anti-foaming agentsinclude high molecular weight silicones and other materials well knownin the art for such use.

[0186] Suitable emulsions may have a wide range of viscosities,depending on the desired product form. Exemplary low viscosityemulsions, which are preferred, have a viscosity of about 50 centistokesor less, more preferably about 10 centistokes or less, most preferablyabout 5 centistokes or less. The emulsion may also contain ananti-foaming agent to minimize foaming upon application to thekeratinous tissue. Anti-foaming agents include high molecular weightsilicones and other materials well known in the art for such use.

[0187] One type of emulsion is a water-in-silicone emulsion.Water-in-silicone emulsions contain a continuous silicone phase and adispersed aqueous phase. Preferred water-in-silicone emulsions of thepresent-invention comprise from about 10% to about-60%, preferably fromabout 5% to about 40%, more preferably from about 10% to about 20%, byweight of a continuous silicone phase. The continuous silicone phaseexists as an external phase that contains or surrounds the discontinuousaqueous phase described hereinafter.

[0188] The continuous silicone phase may contain a polyorganosiloxaneoil. A preferred water-in-silicone emulsion system is formulated toprovide an oxidatively stable vehicle for delivery of a pharmaceuticallyeffective amount of anagent disclosed herein. The continuous siliconephase of these preferred emulsions comprises between about 50% and about99.9% by weight of organopolysiloxane oil and less than about 50% byweight of a non-silicone oil. In an especially preferred embodiment, thecontinuous silicone phase comprises at least about 50%, preferably fromabout 60% to about 99.9%, more preferably from about 70% to about 99.9%,and even more preferably from about 80% to about 99.9%,polyorganosiloxane oil by weight of the continuous silicone phase, andup to about 50% non-silicone oils, preferably less than about 40%, morepreferably less than about 30%, even more preferably less than about10%, and most preferably less than about 2%, by weight of the continuoussilicone phase. These useful emulsion systems may provide more oxidativestability over extended periods of time than comparable water-in-oilemulsions containing lower concentrations of the polyorganosiloxane oil.Concentrations of non-silicone oils in the continuous silicone phase areminimized or avoided altogether so as to possibly further enhanceoxidative stability of the active compound of the invention in thecompositions. Water-in-silicone emulsions of this type are described inU.S. Pat. No. 5,691,380 to Mason et al., issued Nov. 25, 1997.

[0189] The organopolysiloxane oil for use in the composition may bevolatile, non-volatile, or a mixture of volatile and non-volatilesilicones. The term “nonvolatile” as used in this context refers tothose silicones that are liquid under ambient conditions and have aflash point (under one atmospheric of pressure) of or greater than about100 degrees Celsius. The term “volatile” as used in this context refersto all other silicone oils. Suitable organopolysiloxanes can be selectedfrom a wide variety of silicones spanning a broad range of volatilitiesand viscosities. Examples of suitable organopolysiloxane oils includepolyalkylsiloxanes, cyclic polyalkylsiloxanes, andpolyalkylarylsiloxanes, which are known to those skilled in the art andcommercially available.

[0190] The continuous silicone phase may contain one or morenon-silicone oils. Concentrations of non-silicone oils in the continuoussilicone phase are preferably minimized or avoided altogether so as tofurther enhance oxidative stability of the pharmaceutically effectiveagent in the compositions. Suitable non-silicone oils have a meltingpoint of about 25° C. or less under about one atmosphere of pressure.Examples of non-silicone oils suitable for use in the continuoussilicone phase are those well known in the-chemical arts in topicalpersonal care products in the form of water-in-oil emulsions, e.g.mineral oil, vegetable oils, synthetic oils, semisynthetic oils, etc.

[0191] Useful topical compositions of the present invention comprisefrom about 30% to about 90%, more preferably from about 50% to about85%, and most preferably from about 70% to about 80% of a dispersedaqueous phase. In emulsion technology, the term “dispersed phase” is aterm well-known to one skilled in the art which means that the phaseexists as small particles or droplets that are suspended in andsurrounded by a continuous phase. The dispersed phase is also known asthe internal or discontinuous phase. The dispersed aqueous phase is adispersion of small aqueous particles or droplets suspended in andsurrounded by the continuous silicone phase described hereinbefore. Theaqueous phase can be water, or a combination of water and one or morewater soluble or dispersible ingredients. Non-limiting examples of suchoptional ingredients include thickeners, acids, bases, salts, chelants,gums, water-soluble or dispersible alcohols and polyols, buffers,preservatives, sunscreening agents, colorings, and the like.

[0192] The topical compositions of the present invention typicallycomprise from about 25% to about 90%, preferably from about 40% to about80%, more preferably from about 60% to about 80%, water in the dispersedaqueous phase by weight of the composition.

[0193] The water-in-silicone emulsions of the present inventionpreferably comprise an emulsifier. In a preferred embodiment, thecomposition contains from about 0.1% to about 10% emulsifier, morepreferably from about 0.5% to about 7.5%, most preferably from about 1%to about 5%, emulsifier by weight of the composition. The emulsifierhelps disperse and suspend the aqueous phase within the continuoussilicone phase.

[0194] A wide variety of emulsifying agents can be employed herein toform the preferred water-in-silicone emulsion. Known or conventionalemulsifying agents can be used in the composition, provided that theselected emulsifying agent is chemically and physically compatible withessential components of the composition, and provides the desireddispersion characteristics. Suitable emulsifiers include siliconeemulsifiers, e.g., organically modified organopolysiloxanes, also knownto those skilled in the art as silicone surfactants,non-silicon-containing emulsifiers, and mixtures thereof, known by thoseskilled in the art for use in topical personal care products.

[0195] Useful emulsifiers include a wide variety of siliconeemulsifiers. These silicone emulsifiers are typically organicallymodified organopolysiloxanes, also known to those skilled in the art assilicone surfactants. Suitable emulsifiers are described, for example,in McCutcheon's, Detergents and Emulsifiers, North American Edition(1986), published by Allured Publishing Corporation; U.S. Pat. No.5,011,681 to Ciotti et al., issued Apr. 30, 1991; U.S. Pat. No.4,421,769-to Dixon et al., issued Dec. 20, 1983; and U.S. Pat. No.3,755,560 to Dickert et al., issued Aug. 28, 1973.

[0196] Other preferred topical carriers include oil-in-water emulsions,having a continuous aqueous phase and a hydrophobic, water-insolublephase (“oil phase”) dispersed therein. Examples of suitable carrierscomprising oil-in-water emulsions are described in U.S. Pat. No.5,073,371 to Turner et al., issued Dec. 17, 1991; and U.S. Pat. No.5,073,372, to Turner et al., issued Dec. 17, 1991. An especiallypreferred oil-in-water emulsion, containing a structuring agent,hydrophilic surfactant and water, is described in detail hereinafter.

[0197] A preferred oil-in-water emulsion comprises a structuring agentto assist in the formation of a liquid crystalline gel networkstructure. Without being limited by theory, it is believed that thestructuring agent assists in providing rheological characteristics tothe composition which contribute to the stability of the composition.The structuring agent may also function as an emulsifier or surfactant.Preferred compositions of this invention comprise from about 0.5% toabout 20%, more preferably from about 1% to about 10%, most preferablyfrom about 1% to about 5%, by weight of the composition, of astructuring agent. The preferred structuring agents of the presentinvention are selected from the group consisting of stearic acid,palmitic acid, stearyl alcohol, cetyl alcohol, behenyl alcohol, stearicacid, palmitic acid, the polyethylene glycol ether of stearyl alcoholhaving an average of about 1 to about 21 ethylene oxide units, thepolyethylene glycol ether of cetyl alcohol having an average of about 1to about 5 ethylene oxide units, and mixtures thereof.

[0198] The preferred oil-in-water emulsions comprise from about 0.05% toabout 10%, preferably from about 1% to about 6%, and more preferablyfrom about 1% to about 3% of at least one hydrophilic surfactant whichcan disperse the hydrophobic materials in the water phase (percentagesby weight of the topical carrier). The surfactant, at a minimum, must behydrophilic enough to disperse in water. Suitable surfactants includeany of a wide variety of known cationic, anionic, zwitterionic, andamphoteric surfactants. See McCutcheon's. Detergents and Emulsifiers(1986), supra; U.S. Pat. No. 5,011,681 to Ciotti et al., issued Apr. 30,1991; U.S. Pat. No. 4,421,769 to Dixon et al. issued Dec. 20, 1983; andU.S. Pat. No. 3,755,560 to Dickert et al., issued Aug. 28, 1973. Theexact surfactant chosen depends upon the pH of the composition and theother components present. Preferred are cationic surfactants, especiallydialkyl quaternary ammonium compounds, examples of which are describedin U.S. Pat. No. 5,151,209 to McCall et al. issued Sep. 29, 1992; U.S.Pat. No. 5,151,210 to Steuri et al. issued Sep. 29, 1992; U.S. Pat. No.5,120,532 to Wells et al, issued Jun. 9, 1992; U.S. Pat. No. 4,387,090to Bolich Jr., issued Jun. 7, 1983; U.S. Pat. No. 3,155,591 to Hilfer,issued Nov. 3, 1964; U.S. Pat. No. 3,929,678 to Laughlin et al, issuedDec. 30, 1975; U.S. Pat. No. 3,959,461 to Bailey et al., May 25, 1976;McCutcheon's, Detergents & Emulsifiers (North American edition 1979) M.C. Publishing Co.; and Schwartz, et al., Surface Active Agents, TheirChemistry and Technology, New York: Interscience Publishers, 1949.

[0199] Alternatively, other useful cationic emulsifiers includeamino-amides. Non-limiting examples of these cationic emulsifiersinclude stearamidopropyl PG-dimonium chloride phosphate,behenamidopropyl PG dimonium chloride, stearamidopropyl ethyldimoniumethosulfate, stearamidopropyl dimethyl (myristyl acetate) ammoniumchloride, stearamidopropyl dimethyl cetearyl ammonium tosylate,stearamidopropyl dimethyl ammonium chloride, stearamidopropyl dimethylammonium lactate, and mixtures thereof.

[0200] A wide variety of anionic surfactants are also useful herein.See, e.g., U.S. Pat. No. 3,929,678, to Laughlin et al., issued Dec. 30,1975. In addition, amphoteric and zwitterionic surfactants are alsouseful herein.

[0201] The preferred oil-in-water emulsion comprises from about 25% toabout 98%, preferably from about 65% to about 95%, more preferably fromabout 70% to about 90% water by weight of the topical carrier.

[0202] The hydrophobic phase is dispersed in the continuous aqueousphase. The hydrophobic phase may contain water-insoluble or partiallysoluble materials such as are known in the art, including but notlimited to the silicones described herein in reference tosilicone-in-water emulsions, and other oils and lipids such as describedabove in reference to emulsions.

[0203] The topical compositions of the subject invention, including butnot limited to lotions and creams, may comprise a dermatologicallyacceptable emollient. Such compositions preferably contain from about 2%to about 50% of the emollient. As used herein, “emollient” refers to amaterial useful for the prevention or relief of dryness, as well as forthe protection of the skin. A wide variety of suitable emollients areknown and may be used herein. See, e.g., Sagarin, Cosmetics, Science andTechnology, 2nd Edition, Vol. 1, pp. 3243 (1972), which containsnumerous examples of materials suitable as an emollient. A preferredemollient is glycerin. Glycerin is preferably used in an amount of fromor about 0.001 to or about 20%, more preferably from or about 0.01 to orabout 10%, most preferably from or about 0.1 to or about 5%, e.g., 3%.

[0204] Lotions and creams according to the present invention generallycomprise a solution carrier system and one or more emollients. Lotionstypically comprise from about 1% to about 20%, preferably from about 5%to about 10% of emollient; from about 50% to about 90%, preferably fromabout 60% to about 80% water; and a pharmaceutically effective amount ofan agent described herein. A cream typically comprises from about 5% toabout 50%, preferably from about 10% to about 20% of emollient; fromabout 45% to about 85%, preferably from about 50% to about 75% water;and a pharmaceutically effective amount of an agent described herein.

[0205] Ointments of the present invention may comprise a simple carrierbase of animal or vegetable oils or semi-solid hydrocarbons(oleaginous); absorption ointment bases, which absorb water to formemulsions; or water soluble carriers, e.g., a water soluble solutioncarrier. Ointments may further comprise a thickening agent, such asdescribed in Sagarin, Cosmetics, Science and Technology, 2nd Edition,Vol. 1, pp. 72-73 (1972), incorporated herein by reference, and/or anemollient. For example, an ointment may comprise from about 2% to about10% of an emollient; from about 0.1% to about 2% of a thickening agent;and a pharmaceutically effective amount of an agent described herein.

[0206] By way of non-limiting example, 1000 g of topical cream isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, tegacidregular (150 g) (a self-emulsifying glyceryl monostearate fromGoldschmidt Chemical Corporation, New York, N.Y.), polysorbate 80 (50g), spermaceti (100 g), propylene glycol (50 g), methylparaben (1 g),and deionized water in sufficient quantity to reach 1000 gm. The tegacidand spermaceti are melted together at a temperature of 70-80° C. Themethylparaben is dissolved in about 500 g. of water and the propyleneglycol, polysorbate 80, and active compound are added in turn,maintaining a temperature of 75-80° C. The methylparaben mixture isadded slowly to the tegacid and spermaceti melt, with constant stirring.The addition is continued for at least 30 minutes with additionalstirring until the temperature has dropped to 40-45° C. Finally,sufficient water is added to bring the final weight to 1000 g. and thepreparation stirred to maintain homogeneity until cooled and congealed.

[0207] By way of non-limiting example, 1000 g of a topical ointment isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, zincoxide (50 g), calamine (50 g), liquid petrolatum (heavy) (250 g), woolfat (200 g), and enough white petrolatum to reach 1000 g. Briefly, thewhite petrolatum and wool fat are melted and 100 g of liquid petrolatumadded thereto. The pharmaceutically effective amount of an agentdisclosed herein, zinc oxide, and calamine are added to the remainingliquid petrolatum and the mixture milled until the powders are finelydivided and uniformly dispersed. The mixture is stirred into the whitepetrolatum, melted and cooled with stirring until the ointment congeals.

[0208] By way of non-limiting example, 1000 g of an ointment containinga pharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein, lightliquid petrolatum (250 g), wool fat (200 g), and enough white petrolatumto reach 1000 g. Briefly, the pharmaceutically effective amount of anagent disclosed herein is finely divided and added to the light liquidpetrolatum. The wool fat and white petrolatum are melted together,strained, and the temperature adjusted to 45-50° C. The liquidpetrolatum slurry is added, and the ointment stirred until congealed.

[0209] By way of non-limiting example, 1000 ml of an aqueous solutioncontaining a pharmaceutically effective amount of an agent disclosedherein is prepared from the following types and amounts of ingredients:a pharmaceutically effective amount of an agent disclosed herein,polyethylene glycol 4000 (120 g) myristyl-gamma-picolinium chloride (0.2g), polyvinylpyrrolidone (1 g), and enough deionized water to reach 1000milliliters. Briefly, the ingredients are dissolved in the water and theresulting solution is sterilized by filtration.

[0210] By way of non-limiting example, 1000 g of lotion containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of ingredients: apharmaceutically effective amount of an agent disclosed herein,N-methylpyrolidone (40 g), and enough propylene glycol to reach 1000 g.

[0211] By way of non-limiting example, an aerosol containing apharmaceutically effective amount of an agent disclosed herein isprepared from the following types and amounts of materials: apharmaceutically effective amount of an agent disclosed herein, absolutealcohol (4.37 g), dichlorodifluoroethane (1.43 g) anddichlorotetrafluoroethane (5.70 g). Briefly, the pharmaceuticallyeffective amount of an agent disclosed herein is dissolved in theabsolute alcohol and the resulting solution filtered to remove particlesand lint. This solution is chilled to about minus 30° C. Then, to thisis added the chilled mixture of dichlorodifluoromethane anddichlorotetrafluoroethane.

[0212] For oral administration, gelatin capsules or liquid-filled softgelatin capsules can contain the active ingredient and powdered orliquid carriers, such as lactose, lecithin starch, cellulosederivatives, magnesium stearate, stearic acid, and the like. Similardiluents can be used to make compressed tablets. Both tablets andcapsules can be manufactured as sustained release products to providefor continuous release of medication over a period of hours. Compressedtablets can be sugar-coated or film-coated to mask any unpleasant tasteand to protect the tablet from the atmosphere, or enteric-coated forselective, targeted disintegration in the gastrointestinal tract. Liquiddosage forms for oral administration can contain coloring and/orflavoring to increase patient acceptance.

[0213] In general, sterile water, oil, saline, aqueous dextrose(glucose), polysorbate and related sugar solutions and glycols such aspropylene glycol or polyethylene glycols, are suitable carriers forparenteral solutions. Solutions or emulsions for parenteraladministration preferably contain about 5-15% polysorbate 80 orlecithin, suitable stabilizing agents and, if necessary, buffersubstances. Anti-oxidizing agents such as, but not limited to, sodiumbisulfite, sodium sulfite, or ascorbic acid, either alone or combined,are suitable stabilizing agents. Also useful are citric acid and itssalts, and sodium EDTA. In addition, parenteral solutions can containpreservatives including, but not limited to, benzalkonium chloride,methyl- or propyl-paraben, and chlorobutanol.

[0214] Additional examples of particular formulations comprising anactive compound of the present invention are provided below.

[0215] An example of the preparation of a topical gel follows. TABLE 1Topical Gel: Ingredient Percent by Weight Active compound 0.50 Propyleneglycol 20.00 Ethanol 20.00 Carboxyvinyl polymer [Carbomer 940 ™] 1.00Hydroxyethyl cellulose 0.40 Benzyl alcohol 1.00 Sodium hydroxide 1N topH 6 Distilled water Balance

[0216] The components other than sodium hydroxide are combined to yielda homogeneous dispersion. Addition of sodium hydroxide causes themixture to gel yielding a ready-to-use semisolid.

[0217] An example of the preparation of a topical cream follows. TABLE 2Topical Cream: Ingredient Percent by Weight Active compound 0.50 Stearicacid 7.00 Stearyl alcohol 5.00 Cetyl alcohol 2.00 Glycerin 10.00 Sodiumlaurylsulfate 1.00 Propylparaben 0.05 Methylparaben 0.25 Disodiumedetate 0.05 Distilled water Balance

[0218] The first four ingredients are heated to approximately 70° C. toproduce a uniform melt. The remaining ingredients are combined, heatedto approximately 75° C., and added with mixing to the previouslyprepared melt. The emulsion thus formed is subsequently homogenized andcooled to yield a smooth white cream.

[0219] An example of the preparation of a topical lotion follows. TABLE3 Topical Lotion: Ingredient Percent by Weight Active compound 0.50Glyceryl monostearate 1.00 Isopropyl palmitate 4.00 Polyethylene glycol400 distearate 2.00 Glycerin 10.00  Methylparaben 0.10 Sodiumcetylsulfate 5.00 Distilled water Balance

[0220] The first four ingredients are combined and heated toapproximately 70° C., then added with agitation to a mixture of theremaining ingredients, also at about 70° C. The emulsion isappropriately homogenized and cooled to produce a smooth, white,pourable lotion.

[0221] An example of the preparation of a topical solution follows.TABLE 4 Topical Solution: Ingredient Percent by Weight Active compound0.50 Propylene glycol 20.00 Ethanol 50.00 Benzyl alcohol 1.00 Disodiumedetate 0.01 Propyl gallate 0.10 Citric acid 0.20 Sodium hydroxide 1N topH 6 Distilled water Balance

[0222] All ingredients except sodium hydroxide are combined withagitation, and the pH of the resultant solution is adjusted with 1Nsodium hydroxide, to pH 6, to yield a free-flowing, quick-drying topicalsolution.

[0223] The topical formulations presented herein are examples of typicalgel, cream, lotion, or solution dosage forms of active compounds for usein lightening skin. Other optional components can be added or excipientratios can be adjusted to enhance cosmetic acceptability of theformulations. Additionally, these alterations can be made to customizethe composition toward a particular active compound, for example, toensure solubilization or to enhance chemical or physical stability.Optional components would include viscosity adjusters such ascelluloses, emollient oils such as mineral oil or glycerides, humectantssuch as polyols, cosolvents such as isopropyl alcohol or acetone,emulsifying agents of the anionic, cationic and non-ionic types,preservatives, antioxidants, opacifiers, colorants and perfumes.

[0224] An example of the preparation of an oral tablet formulationfollows. TABLE 5 Tablet Formulation: Ingredient Amount (mg) ActiveCompound 25 Lactose 50 Cornstarch (for mix) 10 Cornstarch (paste) 10Magnesium stearate (1%) 5 Total 100

[0225] The active compound, lactose, and cornstarch (for mix) areblended to uniformity. The cornstarch (for paste) is suspended in 200 mLof water and heated with stirring to form a paste. The paste is used togranulate the mixed powders. The wet granules are passed through a No. 8hand screen and dried at 80° C. The dry granules are lubricated with the1% magnesium stearate and pressed into a tablet.

[0226] An example of the preparation of an oral solution follows. TABLE6 Oral Solution: Ingredient Percent by Weight Active Compound 2.0 Ethylalcohol 10.0  Benzyl alcohol 1.0 Peppermint flavor 0.2 Vanillin 0.2Polysorbate 40 0.1 Sucrose 50.0  Purified water Balance

[0227] The ingredients are combined and mixed to form a uniformsolution.

[0228] As will be understood by those in the art, the compositions andpharmaceutical compositions of the invention may be provided as part ofa kit. Kits of the present invention comprise a container comprising oneor more specific compounds and/or pharmaceutical compositions of thepresent invention that lighten skin. The container is designed toprevent contamination, minimize evaporation or drying of thecomposition, etc. Optionally, the kit further comprises printedinstructions as a label or package insert directing the use of theenclosed compound or composition to lighten skin pigmentation. Thecompound or composition may or may not be provided in a preset unit doseor usage amount.

[0229] The ability of compounds of formula I to inhibit tyrosinase maybe determined using any of the following procedures.

[0230] 1. Tyrosinase (DOPA Oxidase) Assay Using Cell Lysate:

[0231] Human melanoma cell line, SKMEL 188 (licensed from MemorialSloan-Kettering), is used in the cell lysate assay and the screen. Inthe assay, compounds and L-dihydroxyphenylalanine (L-DOPA) (100 μg/ml)are incubated with the cell lysates containing human tyrosinase for 8hrs before the plates are read at 405 nm. Most of the compounds offormula I that were tested in this assay exhibited an IC₅₀ of 10 μM orless. For example, the compound of Example 22 below, i.e.,trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate,had an IC₅₀ in this assay of about 2 μm.

[0232] 2. Melanin Assay in Human Primary Melanocytes:

[0233] Compounds are incubated with human primary melanocytes in thepresence of α-melanocyte stimulating hormone (a-MSH) for 2-3 days. Cellsare then lysed with sodium hydroxide and sodium dodecyl sulfate (SDS)and melanin signals are read at 405 nm. Alternatively, ¹⁴C-DOPA is addedto the cells in combination with tyrosinase inhibitors andacid-insoluble ¹⁴C-melanin is quantitated by a scintillation counter.IC₅₀'s reflect the inhibitory potency of the compounds in the newmelanin synthesis that was stimulated by α-MSH.

[0234] 3. Tyrosine Kinase Assay (TK):

[0235] TK assays can be performed using purified tyrosine kinase domainsof c-met, erb-B2, or IGF-r. A specific antibody against phosphorylatedtyrosine residue is used in the assay. Colorimetric signals aregenerated by horseradish peroxidase, which is conjugated to theantibody.

[0236] 4. Human Skin Equivalent Model:

[0237] A mixture of human melanocytes and keratinocytes is grown in anair-liquid interphase. This tissue culture forms a three-dimensionalstructure that histologically and microscopically resembles the humanskin epidermis. Test compounds are added on top of the cells to mimictopical drug application. After incubation with the compounds (10 μM)for 3 days, the cells are washed extensively and lysed for DOPA oxidaseassay.

[0238] 5. IL-1 Assay (Interleukin-1 Assay):

[0239] An IL-1α ELISA assay (R&D system) can be used to evaluate theeffect of compounds on IL-1 secretion in a human skin equivalent model.IL-1α is a pro-inflammatory cytokine and plays a role in UV-induced skininflammation.

[0240] 6. In vivo Study:

[0241] Black or dark brown guinea pigs with homogeneous skin color canbe used in this study. A solution of the test compound of formula 1 (5%in ethanol:propylene glycol, 70:30) and the vehicle control are appliedto the animals twice daily, 5 days per week for 4-8 weeks. Using thisassay, depigmentation can be determined by subtracting the lightreflectance of untreated skin from the light reflectance of treatedskin.

[0242] The present invention is illustrated by the following examples.It will be understood, however, that the invention is not limited to thespecific details of these examples. Melting points are uncorrected.Proton nuclear magnetic resonance spectra (400 MHz ¹H NMR) were measuredfor solutions in d₆-DMSO, CDCl₃, or d₄-MeOH, and peak positions areexpressed in parts per million (ppm) downfield from tetramethylsilane(TMS). The peak shapes are denoted as follows: s, singlet; d, doublet;t, triplet; q, quartet, m, multiplet, b, broad.

[0243] Flash column chromatography (FCC) was carried out on SiO₂.RP-HPLC refers to preparative reverse-phase high-performance liquidchromatography. Mass spectra were obtained using an electrosprayionisation. LCMS analysis was performed using a Waters 2700 autosampler,attached to a Waters 2690 HPLC, using the conditions described below.Mass spectra were obtained on a Micromass Platform LC mass spectrometer,using positive and negative electrospray ionisation. Samples weredissolved in DMSO. Column: Waters Symmetry C18, 3.5 μm, 2.1 × 30 mmMobile Phase A: 95% Water, 5% Acetonitrile, 0.1% Formic acid MobilePhase B: Acetonitrile, 0.1% Formic acid Gradient: 0.0 min  0% B 0.2 min 0% B 3.0 min 90% B 3.5 min 90% B 3.6 min  0% B 4.5 min  0% B Flow: 1.0ml/min Injection: 10 μl DAD: 210-230 nm

[0244] The following examples are illustrative only, and are notintended to limit the scope of the present invention.

EXAMPLES Preparation 1 3-Benzyloxy-2-cyclohexen-1-one

[0245] To a round bottomed flask equipped with Dean-Stark apparatus wasadded 1,3-cyclohexanedione (60.0 g), toluene (450 ml), ptoluenesulfonicacid monohydrate (1.35 g) and benzyl alcohol (52.6 g, 487). Theresulting solution was heated to reflux temperature for 12 hr. Thereaction mixture was cooled to room temperature and then washed withsaturated aqueous sodium carbonate solution (2×100 ml). The organiclayer was then washed with brine (100 ml), dried over magnesium sulfate,filtered and concentrated in vacuo, affording a brown oil (94.9 g) whichcrystallised upon standing for 17 hr. The crude crystalline material wasslurried in isopropyl ether (20 ml). The mixture was filtered and thecrystalline material was washed with ice cold isopropyl ether (3×30 ml),then with cold petroleum ether (2×20 ml). The resulting peach-coloredcrystalline solid was dried overnight under reduced pressure, furnishingthe title compound (74.4 g, 76%). m/z (ES⁺) 203 (M+H⁺).

Preparation 2(±)-3-Benzyloxy-6(8-hydroxy-1,4-ioxaspiro[4.5]dec-8-yl)-2-cyclohexen-1-one

[0246] To a round-bottomed flask was added anhydrous tetrahydrofuran(600 ml) and diisopropylamine (38.1 ml). The stirred solution was cooledto −78° C. and nbutyl lithium (113.4 ml, 2.4 M in cyclohexanes) wasadded dropwise via syringe in 20 ml portions. The resulting yellowsolution was stirred for 35 min at −78° C., then3-benzyloxy-2-cyclohexen-1-one (50.0 g) was added as a solution inanhydrous tetrahydrofuran (100 ml). The solution was stirred for 1 hrprior to the addition of cyclohexane-1,4-dione monoethylene ketal (38.7g) as a solution in anhydrous tetrahydrofuran (100 ml). The solution wasstirred for 2 hr at −78° C., then allowed to warm slowly to roomtemperature over 1 hr. Saturated aqueous ammonium chloride (80 ml) wasadded, followed by dichloromethane (700 ml), and the mixture was stirreduntil no solids remained. The layers were separated and the aqueousphase extracted with dichloromethane (2×100 ml). The combined organiclayers were washed with brine (50 ml), dried over magnesium sulfate,then concentrated in vacuo. Trituration of the resulting solid withmethanol afforded the title compound (78.4 g, 88%). m/z (ES⁺) 359(M+H⁺).

Preparation 3(±)-1-Benzyloxy-6-bromo-3-(1.4-dioxaspiro[4.5]dec-8-yl)-2-oxabicyclo[2.2.2]octan-5-one

[0247] A round bottomed flask was charged with(±)-3-benzyloxy(8-hydroxy-1,4-dioxaspiro[4.5]decyl)-2-cyclohexen-1-one(78.4 g) and dichloromethane (600 ml). To the stirred solution was addedN-bromosuccinimide (40.9 g) in one portion, followed by aqueoushydrobromic acid (3 drops, 48% solution) when no more solid remained.The resulting solution was stirred at room temperature for 2 hr thenpoured into a separating funnel containing aqueous sodium metabisulfitesolution (150 ml) and dichloromethane (200 ml), then the funnel wasshaken vigorously. The layers were separated and the organic layer waswashed with brine (200 ml), dried over magnesium sulfate, filtered, thenconcentrated in vacuo to give a solid. Trituration with methanol (500ml) afforded the title compound (82.8 g, 86%) as a white solid. m/z(ES⁺) 437 and 439 [(1:1), M+H+].

Preparation 4 5-Benzyloxy-2-(1,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol

[0248] A round bottomed flask was charged with(±)-1-benzyloxybromo-3-(1,4-dioxaspiro[4.5]decyl)₂-oxabicyclo[2.2.2]octan-5-one(13.8 g) and anhydrous N,N-dimethylformamide (140 ml). To the stirredsolution was added 1,8-diazabicyclo[5.4.0]undec -7-ene (9.92 ml) in oneportion. The solution turned dark brown in colour immediately and wasthen heated to 140° C. for 12 hr with vigorous stirring. The reactionmixture was allowed to cool to room temperature and most of the solventwas removed under reduced pressure. The remaining oil was partitionedbetween ethyl acetate (200 ml) and water (100 ml), then the layers wereseparated and the aqueous phase was extracted with ethyl acetate (3×50ml). The combined organic layers were back-extracted with water (3×30ml) to remove any residual N,N-dimethylformamide. The organic phase waswashed with brine (20 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo to afford a brown oily solid, which was adsorbedonto silica gel. Purification via flash column chromatography (SiO₂,ethyl acetate/petroleum ether, 1:1, v/v) furnished the title compound(7.1 g, 66%) as a white solid. m/z (ES⁺) 339 (M+H⁺).

Preparation 5 4-(2,4-Dihydroxyphenyl)cyclohexanone

[0249] A round bottomed flask was charged with4-(1,4-dioxaspiro[4.5]decyl)-1,3-benzenediol (11.3 g), acetone (250 ml)and water (50 ml). To the stirred solution was added pyridiniumptoluenesulfonate (1.14 g) in one portion and the reaction mixture wasthen heated to reflux, temperature for 8 hr. After allowing the reactionmixture to cool to room temperature, most of the acetone was removed invacuo and the remaining mixture was partitioned between ethyl acetate(200 ml) and water (50 ml). The aqueous layer was extracted with ethylacetate (3×50 ml) and the combined organic layers were washed with brine(30 ml), dried over magnesium sulfate, filtered and concentrated underreduced pressure to afford an off white powder. After washing the powderwith dichloromethane (100 ml) and removing excess solvent under reducedpressure, the title compound (9.30 g, 100%) was obtained as an off-whitepowder. m/z (ES⁺) 207 (M+H⁺).

Preparation 64-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone

[0250] 4-(2,4-Dihydroxyphenyl)cyclohexanone (400 mg) was dissolved indimethyl formamide (3 ml) with stirring. tert-Butyldimethylsilylchloride (704 mg), imidazole (660 mg) and 4-dimethylaminopyridine (3 mg)were added sequentially. After 4 hr, the solvent was removed in vacuoand the residue partitioned between ethyl acetate (20 ml) and water (5ml). The aqueous phase was extracted with ethyl acetate (2×10 ml), andthe combined organic phases were washed with brine (10 ml), dried overanhydrous magnesium sulfate, and concentrated under reduced pressure togive a brown oil. Purification via flash column chromatography (SiO₂eluting with ethyl acetate/petroleum ether, 1:9 v/v) furnished the titlecompound as white flakes (750 mg, 89%). m/z (ES⁺) 435 (M+1)⁺.

Preparation 7cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]Amine

[0251] To a round bottomed flask was charged4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (3.20g), 1,2-dichloroethane (85 ml), and to the stirred solution was addedbenzylamine (0.97 ml) as a solution in 1,2-dichloroethane (20 ml)followed by activated powdered 4A molecular sieves (5.80 g) and thereaction mixture stirred for 2.5 hr.Tetramethylammoniumtriacetoxyborohydride (2.90 g) was added in oneportion and the reaction mixture stirred for 64 hr at room temperature.Aqueous sodium hydroxide solution (30 ml, 0.4M) was added and vigorousstirring was continued for 0.5 hr. The reaction mixture was filteredthrough celiie, washing with dichloromethane (100 ml). The layers wereseparated and the aqueous layer was extracted with dichloromethane (2×50ml). The combined organic phases were washed with brine (100 ml), driedover magnesium sulfate, filtered and concentrated in vacuo affordingthe-crude product. Purification via flash column chromatography (SiO₂,ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4, then 3:7v/v) furnished the title compound (2.69 g, 70%) as a pale yellow oil.δ_(H)(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.77 (9H, s), 0.83 (9H, s),1.31 (1H, br), 1.39 (4H, m), 1.52 (2H, m), 1.70 (2H, m), 2.69 (1H, m),2.75 (1H, m), 6.10 (1H, d), 6.23 (1H, dd), 6.84 (1H, d), 7.15 (5H, m).

Preparation 8N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]Amine

[0252] To a round bottomed flask was added4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (817mg). Dichloromethane (50 ml) was added followed by benzylamine (0.82 ml,7.52 mmol) and activated 4 Å molecular sieves (10.0 g). The reactionmixture was stirred vigorously for 15 hr, then dichloromethane (50 ml)was added and the reaction mixture filtered through celite, washing withdichloromethane (50 ml). The filtrate was concentrated in vacuoaffording the title compound (1.00 g, 86%) as a yellow oil. 8,(CDCl₃)0.19 (6H, s), 0.26 (6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.51 (1H, m),1.72 (1H, m), 2.03 (2H, m), 2.45 (1H, m), 2.60 (1H, m), 3.04 (1H, m),3.22 (1H, m), 4.55 (1H, d), 4.60 (1H, d), 6.31 (1H, d), 6.41 (1H, dd),6.93 (1H, d), 7.33 (5H, m).

Preparation 9trans-N-Benzyl-N-[4(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine

[0253] To a round bottomed flask was addedN-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]amine (4.00 g) andtetrahydrofuran (480 ml) followed by methanol (120 ml). To the solutionwas added sodium borohydride (1.16 g) and the reaction mixture stirredfor 17 hr. The reaction mixture was then diluted with diethyl ether (600ml) and aqueous sodium hydroxide (400 ml, 0.4M) added. After stirringfor 10 min, the layers were separated and the aqueous layer extractedwith dichloromethane (3×100 ml). The combined organic phases were washedwith brine (50 ml), dried over magnesium sulfate and concentrated invacuo to give a yellow oil. Purification via flash column chromatography(SiO₂, ethyl acetate/petroleum ether, gradient elution using 1:9, 1:4,then 3:7, v/v) furnished the title compound (2.09 g, 54%) as a creamsolid. bH(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.80 (9H, s), 0.85 (9H, s),1.18 (4H, m), 1.66 (2H, m), 1.87 (2H, m), 2.19 (1H, m), 2.68 (1H, M),6.12 (1H, d), 6.23 (1H, dd), 6.77 (1H, d), 7.17 (5H, m).

Preparation 10trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

[0254] To a round bottom flask was addedtrans-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine (500 mg, 0.95 mmol) and ethanol (20 ml). To the stirredsolution was added palladium (10% w/w on activated carbon, 200 mg, 0.19mmol) as a slurry in ethanol (5 ml). The reaction vessel was evacuated,then placed under hydrogen (10 cycles). The reaction mixture was stirredvigorously under an atmosphere of hydrogen for 18 hr, then filteredthrough a celite plug, washing with methanol (100 ml). The solvent wasremoved in vacuo affording the title compound (402 mg, 97%) as acolourless oil. δ_(H)(CDCl₃) 0.01 (6H, s), 0.05 (6H, s), 0.78 (9H, s),0.82 (9H, s), 1.08 (2H, m), 1.21 (2H, m), 1.62 (2H, m), 1.78 (2H, m),2.59 (2H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.78 (1H, d).

Preparation 11cis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine

[0255] To a round bottom flask equipped with magnetic stirrer was addedcis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(700 mg) and ethanol (30 ml). To the stirred solution was addedpalladium (10% w/w on activated carbon, 283 mg) as a slurry in ethanol(5 ml). The reaction vessel was evacuated then placed under hydrogen (10cycles). The reaction mixture was stirred vigorously under an atmosphereof hydrogen for 18 hr then filtered through a celite plug, washing withmethanol (100 ml). The solvent was removed in vacuo affording the titlecompound (561 mg, 97%) as a colourless oil. δ_(H)(CDCl₃) 0.01 (6H, s),0.04 (6H, s), 0.78 (9H, s), 0.83 (9H, s), 1.21-1.55 (10H, m), 2.64 (1H,m), 3.05 (1H, m), 6.11 (1H, d), 6.22 (1H, dd), 6.84 (1H, d).

Preparation 12 1-Bromo-2,4-bis(methoxymethoxy)benzene

[0256] A round bottomed flask was loaded with 4-bromoresorcinol (9.45 g)and CH₂Cl₂ (50 ml). The stirred suspension was cooled to 0° C. anddiisopropylamine (19.1 ml) was added in one portion. Stirring of thesolution was continued for a further 10 min before methyl chloromethylether (10.7 ml) was added. The resulting yellow solution was thenallowed to warm to room temperature overnight. Ammonium hydroxidesolution (50 mL, 50%) was poured into the reaction vessel and stirringwas continued for 1 hr. The mixture was poured into a separating funneland the phases separated. The aqueous phase was then extracted withCH₂Cl₂ (3×30 ml) and the combined organics washed with brine (20 ml),dried over anhydrous magnesium sulfate, filtered and concentrated invacuo affording an orange oil. Purification was achieved by flash columnchromatography, (SiO₂, ethyl acetate/petroleum ether, 1:1, v/v),furnishing the title product (10.7 g, 77%) as a pale yellow oil.δ_(H)(CDCl₃) 7.42 (1H, d), 6.88 (1H, d), 6.64 (1H, dd), 5.24 (2H, s),5.15 (2H, s), 3.53 (3H, s), 3.48 (3H, s).

Preparation 138-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol

[0257] A round bottomed flask was loaded with1-bromo-2,4-bis(methoxymethoxy)benzene (2.00 g) and THF (50 mL).N,N,N′,N′-Tetramethylethylene diamine (2.3 ml) was added and thesolution was cooled to −78° C. n-Butyl lithium (9.5 ml, 1.6M in hexane)was added. The resulting solution was stirred for 1 hr at −78° C. and1,4-cyclohexanedione monoethylene ketal (1.35 g) was added as a solutionin THF (25 ml). The-resulting solution was stirred at −78° C. for 1 hrand then allowed to warm to room temperature overnight. Hydrochloricacid (20 ml, 2M) was added and the reaction mixture stirred vigorouslyfor 15 min. Ethyl acetate (100 ml) was added and the mixture poured intoa separating funnel. The phases were separated and the aqueous phase wasextracted with ethyl acetate (3×20 ml). The combined organic phases werewashed with brine (20 ml), dried over anhydrous magnesium sulfate,filtered and concentrated affording an orange oil, which was purified byflash column chromatography (SiO₂, ethyl acetate/petroleum ether, 45:55,v/v). The title product (1.42 g, 56%) was isolated as a colourless oil.m/z (ES⁺) 337 (M−H₂O+H+); δ_(H) (CDCl₃) 1.61-1.64(2H, m), 2.00-2.18(6H,m), 3.44(3H, s), 3.48(3H, s), 3.90-3.97(4H, m), 5.11(2H, s), 5.24(2H,s), 6.64(1H, dd), 6.82(1H, d), 7.20(1H, d).

Preparation 148-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene

[0258] 8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decan-8-ol(1.40 g) was placed in a round bottomed flask fitted with Dean-Starkapparatus. Toluene (30 ml) was added, followed by camphor sulphonic acid(10 mg). The stirred solution was then heated under reflux for 1 hr,cooled, and saturated aqueous sodium bicarbonate solution (10 ml) added.The mixture was poured into a separating funnel and the phasesseparated. The aqueous phase was extracted with ethyl acetate (2×15 ml)and the combined organics were washed with brine (15 ml), dried overanhydrous magnesium sulphate, filtered and then concentrated in vacuoyielding an orange oil, which was purified by flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 45:55, v/v) toafford the title product (0.94 g) as a colourless oil. δ_(H) (CDCl₃)1.84 (2H, t), 2.41-2.43 (2H, m), 2.56-2.62 (2H, m), 3.47 (6H, s),3.98-4.02 (4H, m), 5.13 (4H, s), 5.58-5.63 (1H, m), 6.64 (1H, dd), 6.78(1H, d), 7.08 (1H, d).

Preparation 158-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]decane

[0259] 8-[2,4-Bis(methoxymethoxy)phenyl]-1,4-dioxaspiro[4.5]dec-7-ene(0.950 g) and palladium (200 mg, 10% on carbon) were stirred under anatmosphere of hydrogen for 15 hr. The mixture was then filtered througha plug of Celite, washing with ethyl acetate. The filtrate was thenevaporated to dryness, affording the desired product (0.955 g, 100%) asa colourless oil. δ_(H) (CDCl₃) 1.67-1.87 (8H, m), 2.90-2.99 (1H, m),3.46 (3H, s), 3.48 (3H, s), 3.97 (4H, s), 5.12 (2H, s), 5.18 (2H, s),6.65 (1H, dd), 6.78 (1H, d), 7.12 (1H, d).

Preparation 16 4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexanone

[0260] A round bottomed flask was charged with8-[2,4-bis(methoxymethoxy)phenyl]-1,4-dicxaspiro[4.5]decane (3.20 g) andmethanol (50 ml). Over a 20 min period, aqueous hydrochloric acid (50ml, 1 M) was added to the stirred solution, at room temperature and thereaction mixture stirred for 1.5 hr. Solid sodium bicarbonate was addeduntil the reaction mixture was neutralised and the solvent was removedunder reduced pressure. The residue was partitioned between ethylacetate (30 ml) and water (10 ml), and the aqueous layer was extractedwith ethyl acetate (3×20 ml). The combined organic layers were washedwith brine (10 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. The crude product was purified via flash columnchromatography (SiO₂, ethyl acetate/petroleum ether, 1:4, v/v),affording the title compound (2.20 g, 60%) as a white powder.δ_(H)(CDCl₃) 1.85-1.96 (2H, m), 2.14-2.22 (2H, m), 2.46-2.59 (4H, m),3.39 (1H, tt), 3.49 (3H, s), 3.52 (3H, s), 5.16 (2H, s), 5.23 (2H, s),6.67-6.71 (1H, m), 6.85 (1H, m), 7.08 (1H, d).

Preparation 17(±)-{4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexylidene}Acetic Acid

[0261] To a round bottomed flask was addedtrimethylsilyidiethylphosphonoacetate (1.08 ml) and tetrahydrofuran (25ml). The solution was cooled to 0° C. and n-butyl lithium (1.80 ml, 2.2Min cyclohexanes) was added dropwise and the reaction mixture allowed towarm to room temperature and stirred for 17 hr.4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (750 mg) was added as asolution in tetrahydrofuran (25 ml). After 2 hr at room temperature, themixture was poured into a separating funnel containing aqueous sodiumhydroxide solution (10 ml, 10% w/v). After extracting with diethyl ether(10 ml), the aqueous layer was acidified by adding concentratedhydrochloric acid (10 ml), and extracted with diethyl ether (3×20 ml).The combined organic layers were washed with water (10 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo affording thetitle compound (422 mg, 52%) as an oil. δ_(H)(CDCl₃) 1.86 (2H, m),2.00-2.13 (4H, m), 2.42 (2H, m), 3.19 (1H, m), 3.48 (3H, s), 3.51 (3H,s), 5.14 (2H, s), 5.21 (2H, s), 5.71 (1H, s), 6.67 (1H, dd), 6.81 (1H,d), 7.05 (1H, d).

Preparation 18(±)-{4-[2,4-Bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile

[0262] To a round bottomed flask equipped was added sodium hydride (40mg, 60% dispersion in mineral oil) and 1, 2-dimethoxyethane (10 ml).Diethyl cyanomethylphosphonate (102 μl, 0.95 mmol) was added and thereaction mixture allowed to warm to room temperature.4-[(2,4-Bis(methoxymethoxy)phenyl)]cyclohexanone (200 mg) was added as asolution in 1,2-dimethoxyethane (10 ml) and the reaction mixture stirredfor 17 hr at room temperature. The reaction mixture was poured into aseparating funnel containing water (50 ml) and diethyl ether (50 ml).The layers were separated and the aqueous phase extracted with diethylether (2×20 ml). The combined organic layers were washed with brine (20ml), dried over magnesium sulfate, filtered and concentrated in vacuo,to give an oil. Purification via flash column chromatography (SiO₂-ethylacetate/petroleum ether, 1:2, v/v) afforded the title compound (141 mg,66%) as a pale yellow oil. δ_(H)(CD₃OD) 1.57-1.70 (2H, m), 2.02-2.25(2H, m), 2.34-2.49 (2H, m), 2.60 (1H, m), 3.03 (1H, m), 3.24 (1H, m),3.47 (3H, s), 3.52 (3H, s), 5.17 (2H, s), 5.23(2H, s), 5.33 (1H, s),6.68 (1H, dd), 6.83 (1H, d), 7.09 (1H, d).

Preparations 19 and 20trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol;cis-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol

[0263] Sodium borohydride (164 mg) was added to a stirred solution of4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (1.57 g)in ethanol (50 ml) at 0° C. After 18 hr at room temperature, the mixturewas partitioned between 2M HCl (20 ml), water (40 ml) and ethyl acetate(50 ml) and the aqueous layer was re-extracted with ethyl acetate (2×50ml). The combined organic extracts were washed with brine (40 ml), driedover magnesium sulfate and evaporated in vacuo. The residue was purifiedusing flash column chromatography (SiO₂, ethyl acetate/petrol, 3:17 v/v)to give the trans-title compound as a white solid (546 mg, 35%), and thecis-title compound as a white solid (83 mg, 5%).

[0264] trans—δ_(H) (CDCl₃) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s),1.02 (9H, s), 1.18-1.22 (4H, m), 1.80-1.84 (3H, m), 2.00-2.05 (2H, m),2.78-2.86 (1H, m), 3.60-3.70 (1H, m), 6.28 (1H, d), 6.39 (1H, dd), 6.94(1H, d).

[0265] cis—oil. δ_(H) (CDCl₃) 0.18 (6H, s), 0.22 (6H, s), 0.98 (9H, s),1.02 (9H, s), 1.58-1.78 (6H, m), 1.84-1.92 (2H, m), 2.70-2.80 (1H, m),4.12 (1H, bs), 6.28 (1H, d), 6.40 (1H, dd), 7.02 (1H, d).

Preparations 21 and 22 cis-O-Benzoyl-N-[4-2,4bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine;cis-N-[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzamide

[0266] A round bottomed flask was charged withcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(1.0 g), dichloromethane (15 ml) and buffer (pH 10.5, 0.05M NaHCO₃/0.1NaOH) (20 ml). Dibenzoyl peroxide (1.19 g) in dichloromethane (5 ml) wasadded dropwise and the resulting mixture stirred for 17 hr. The mixturewas diluted with dichloromethane (20 ml) and the organic layerseparated, washed with brine (10 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether, 1:7, v/v) affordedpreparation 19 (1.26 g, 53%) as a colourless solid. δ_(H) (CDCl₃) 0.21(6H, s), 0.24 (6H, s), 1.10 (9H, s), 1.13 (9H, s), 1.62-1.90 (8H, m),2.98 (1H, m), 3.48 (1H, m), 6.35 (1H, d), 6.43 (1H, dd), 7.10 (1H, d),7.48 (2H, m), 7.60 (1H, m), 8.02 (1H, d) and 8.05 (1H, d). Furtherelution (ethyl acetate/petroleum ether, 1:2, v/v) afforded preparation20 (0.47 g, 35%) as a colourless solid. δ_(H) (CDCl₃) 0.21 (6H, s), 0.26(6H, s), 1.09 (9H, s), 1.13 (9H, s), 1.45-1.60 (2H, m), 1.73-1.88 (4H,m), 2.00-2.11 (2H, m), 2.98 (11H, m), 4.40 (1H, m), 6.32 (1H, d), 6.37(1H, d), 6.44 (1H, dd), 7.00 (1H, d), 7.43-7.55 (4H, m) and 7.80 (1H,d).

Preparation 23cis-O-Benzoyl-N-benzyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine

[0267] A round bottomed flask was charged withcis-N-Benzyl-N-[42,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(0.115 g), dichloromethane (2 ml) and buffer (pH 10.5, 0.05M NaHCO₃/0.1NaOH) (3 ml). Dibenzoyl peroxide (0.106 g) in dichloromethane (1 ml) wasadded dropwise and the resulting mixture stirred rapidly for 17 hr. Themixture was diluted with dichloromethane (10 ml) and the organic layerseparated, washed with brine (5 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether, 1:7, v/v) affordedthe title compound (0.083 g, 59%) as a gum. δ_(H) (CDCl₃) 0.21 (6H, s),0.24 (6H, s), 1.00 (9H, s), 1.04 (9H, s), 1.50-1.78 (4H, m), 2.00-2.12(4H, m), 3.00 (1H, m), 3.20 (1H, m), 4.29 (2H, s), 6.28 (1H, d), 6.44(1H, dd), 7.20-7.57 (9H, m) and 7.95 (2H, d).

Preparation 24 trans-O-Benzoyl-benzyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine

[0268] A round bottomed flask equipped was charged withtrans-Nbenzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(0.25 g), dichloromethane (4 ml) and buffer (pH 10.5) (6 ml). Dibenzoylperoxide (0.23 g) in dichloromethane (2 ml) was added and the resultingmixture stirred for 72 hr. The mixture was diluted with dichloromethane(15 ml) and the organic layer separated, washed with brine (5 ml), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash chromatography (SiO₂, ethyl acetate/petroleum ether, 1:7, v/v)afforded the title compound (0.166 g, 54%) as a colourless gum. δ_(H)(CDCl₃) 0.12 (6H, s), 0.19 (6H, s), 1.00 (9H, s), 1.04 (9H, s),1.18-1.36 (2H, m), 1.50-1.65 (2H, m), 1.85 (2H, m), 2.10 (2H, m), 2.68(1H, m), 2.94 (1H, m), 4.19 (2H, s), 6.21 (1H, d), 6.32 (1H, dd), 6.97(1H, d), 7.12-7.24 (3H, m) 7.29-7.37 (4H, m), 7.45 (1H, m) and 7.83 (2H,m).

Preparation 25 trans-O-Benzoyl-N[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine

[0269] A round bottomed flask was charged withtrans(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(0.156 g), dichloromethane (2 ml) and buffer (pH 10.5, 0.05M NaHCO₃/0.1NaOH) (3 ml). Dibenzoyl peroxide (0.186 g) in dichloromethane (1 ml),wasadded and the resulting mixture-stirred for 4 hr. The mixture wasdiluted with dichloromethane (10 ml) and the organic layer separated,washed with brine (5 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether, 1:7, v/v) afforded the title compound(0.116 g, 54%) as a colourless oil. δ_(H) (CDCl₃) 0.21 (6H, s), 0.24(6H, s), 0.98 (9H, s), 1.03 (9H, s), 1.27-1.40 (4H, m), 1.86 (2H, m),2.08 (2H, m), 2.79 (1H, m), 3.08 (1H, m), 6.18 (1H, d), 6.32 (1H, dd),6.86 (1H, d) and 7.33-7.88 (5H, m).

Preparation 26syn-8-(2,4-bis{[tert-Butyl(dimethylsilyl)]oxy}phenyl)-1-oxaspiro[4.5]decan-2-one

[0270] A round bottomed flask was charged with4-(2,4-Bis{[tert-butyl(dimethyl) silyl]oxy}phenyl)cyclohexanone (0.15 g,0.34 mmol), ethyl acrylate (0.05 ml), methanol (2 ml) and THF (4 ml) andsamarium diiodide in THF (0.1 M, 25 ml) added. After stirring for 17 hr,the reaction mixture was concentrated to approximately 25% of theoriginal volume in vacuo. The mixture was diluted with a mixture ofwater (10 ml) and saturated aqueous sodium thiosulfate (10 ml) andextracted with diethyl ether (3×10 ml). The combined organic extractswere washed with brine (10 ml), dried over magnesium sulfate, filteredand concentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether, 1:3, v/v) afforded the title compound(0.04 g, 24%) as a colourless gum. oil. δ_(H) (CDCl₃) 0.22 (6H, s), 0.27(6H, s), 0.96 (9H, s), 1.03 (9H, s), 1.40-1.53 (2H, m), 1.82-1.94 (6H,m), 2.18 (2H, t), 2.62 (2H, t), 2.90 (1H, m), m), 6.33 (1H, d), 6.42(1H, dd) and 6.96 (1H, d).

Preparation 27trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylPhenylcarbamate

[0271] N,N-Diisopropylethylamine (100 μl) and phenylisocyanate (55 μl)were added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (50mg) in anhydrous dichloromethane (2 ml). After 96 hr at 40° C., thereaction mixture was partitioned between ethyl acetate (50 ml) and water(50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml).The combined organic extracts were washed with brine (50 ml); dried overmagnesium sulfate and evaporated in vacuo. The residue was purifiedusing flash column chromatography (SiO₂, ethyl acetate/petrol, 1:2 v/v)to give the title compound (50 mg, 79%) as a pale yellow gum. SH (CDCl₃)0.00 (6H, s), 0.06 (6H, s), 0.80 (9H, s), 0.83 (9H, s), 1.30-1.40 (4H,m), 1.70-1.75 (2H, m), 2.00-2.05 (2H, m), 2.60-2.70 (1H, m), 4.55-4.65(1H, m), 6.10 (1H, d), 6.23 (1H, dd), 6.40 (1H, s), 6.76-7.20 (5H, m).

Preparation 28tert-Butyl[5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy]Dimethylsilane

[0272] To a round bottomed flask was added methyltriphenylphosphoniumbromide (0.99 g) and tetrahydrofuran (30 ml). The resulting suspensionwas cooled to 0° C. and potassium tert-butoxide (0.31 g) was added inone portion. The resulting solution was stirred at 0° C. for 0.5 hr,then 4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone(0.60 g) added as a solution in tetrahydrofuran (10 ml). The solutionwas stirred for 1 hr at 0° C., then allowed to warm to room temperatureand stirred for 15 hr. The reaction mixture was partitioned betweenethyl acetate (20 ml) and saturated ammonium chloride solution (20 ml).The layers were separated and the aqueous layer extracted with ethylacetate (2×20 ml). The combined organic phases were washed with brine(20 ml), dried over magnesium sulfate, filtered and concentrated invacuo. Purification via flash chromatography (SiO₂, ethylacetate/petroleum ether, 1:9 v/v) furnished the title compound (0.56 g,93%) as a colourless oil. δ_(H) (CDCl₃): 0.17 (6H, s), 0.24 (6H, s),0.97 (9H, s), 1.03 (9H, s), 1.34-1.47 (2H, m), 1.86-1.94 (2H, m),2.10-2.20 (2H, m), 2.35-2.43 (2H, m), 3.00 (1H, ft), 4.64 (2H, m), 6.29(1H, d), 6.39 (1H, dd), 6.94 (1H, d).

Preparation 29trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenylpropanoate

[0273] To a round bottomed flask was addedN-(tert-butoxycarbonyl)-L-phenylalanine (109 mg) and dichloromethane (10ml). To the solution was added diisopropylcarbodiimide (64 μl),trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (150mg) and 4-dimethyl aminopyridine (catalytic). The solution was stirredat room temperature for 15 hr. The reaction mixture was partitionedbetween water (20 ml) and dichloromethane (30 ml), the layers wereseparated and the aqueous phase was extracted with dichloromethane (2×30ml). The combined organic phases were washed with brine (20 ml), driedover magnesium sulfate, filtered and concentrated in vacuo. Purificationvia flash chromatography (SiO₂, ethyl acetate/petroleum ether, 1:19 v/v)furnished the title compound (236 mg, 100%) as a yellow oil. δ_(H)(CDCl₃): 0.18 (6H, s), 0.23 (6H, s), 0.97 (9H, s), 1.03 (9H, s),1.35-1.47 (13H, m), 1.80-1.90 (2H, m), 1.95-2.07 (2H, m), 2.77-2.86 (1H,m), 3.05-3.12 (2H, m), 4.49-4.58 (1H, m), 4.73-4.82 (1H, m), 4.93-5.00(1H, m), 6.28 (1H, d), 6.40 (1H, dd), 6.93 (1H, d), 7.15 (2H, d),7.19-7.31 (3H, m).

Preparation 30 Benzyl[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]acetate

[0274] To a round bottomed flask was added4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (1.09g), xylene (65 ml) and benzyl (triphenylphosphoranylidene) acetate (4.20g) and the reaction mixture was heated under reflux for 13 hr. Thesolvent was removed in vacuo and the residue triturated with petroleumether (3×150 ml), and the combined organic phases were concentrated invacuo. Purification via flash chromatography (SiO₂, petroleumether/ethyl acetate, gradient elution using 100, 99:1, 70:1 then 50:1,v/v) furnished the title compound (0.76 g, 54%) as a white solid. m/z(ES⁺) 467 (M+H⁺).

Preparation 31N′-[4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide

[0275] To a round bottomed flask was added4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexanone (0.5 g)and ethanol (10 ml), and the solution heated to allow dissolution. Thestirred solution was cooled to 30° C., p-toluenesulfonyl hydrazide (0.24g) was added, and the reaction mixture stirred at room temperature for1.5 hr. The reaction mixture was filtered, and the filtrate wasconcentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether 3:7 v/v) furnished the title compound(0.60 g, 87%) as a white solid. oil. δ_(H) (CDCl₃): 0.18 (6H, s), 0.22(6H, s), 0.95 (9H, s), 0.99 (9H, s), 1.37-1.49 (1H, m), 1.49-1.62 (1H,m), 1.84-2.02 (3H, m), 2.17-2.27 (1H, m), 2.43 (3H, s), 2.53-2.61 (1H,m), 2.74-2.82 (1H, m), 3.07 (1H, tt), 6.28 (1H, d), 6.38 (1H, dd), 6.86(1H, d), 7.13 (1H, br s), 7.31 (2H, d), 7.86 (2H, d).

Preparation 32trans-N-[4(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-nitrobenzamide

[0276] To a round bottomed flask was addedtrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(80 mg) and dichloroethane (7 ml), and the reaction mixture heated to40° C. To the stirred solution was added triethylamine (100 μl), asolution of 3-nitrobenzoyl chloride (101 mg) intetrahydrofuran/dichloromethane (6 ml, 1:1 v/v) and 4-dimethylaminopyridine (catalytic). The reaction mixture was heated at 40° C. for 24hr, and then room temperature for 24 hr. The reaction mixture wasdiluted with dichloromethane (20 ml) and aqueous sodium hydroxide (16ml, 0.5M) was added. After stirring for 0.2 hr, the layers wereseparated and the aqueous layer extracted with dichloromethane (2×10ml). The combined organic phases were washed with saturated sodiumhydrogen carbonate solution (15 ml) and brine (16 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether, gradientelution using 1:10, 1:8, 1:5, then 1:4, v/v) furnished the titlecompound (52 mg, 49%) as a colourless gum. ⁶H (CDCl₃): 0.18 (6H, s),0.24 (6H, s), 0.97 (9H, s), 1.03 (9H, s), 1.34-1.61 (4H, m), 1.87-1.96(2H, m), 2.17-2.27 (2H, m), 2.88 (1H, tt), 4.01-4.13 (1H, m), 6.08 (1H,d), 6.29 (1H, d), 6.43 (1H, dd), 6.97 (1H, d), 7.65 (1H, t), 8.18 (1H,d), 8.35 (1H, d), 8.57 (1H, s).

Preparation 33 cis-N-Benzoyloxy-N[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-cyanobenzamide

[0277] General Procedure A

[0278] A round bottomed flask was charged withcis-O-benzoyl-N[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine(0.05 g), dichloromethane (2 ml), triethylamine (0.1 ml) and3-cyanobenzoyl chloride (0.044 g). After stirring for 1 hr, the mixturewas diluted with dichloromethane (10 ml) and washed with 2M HCl (5 ml).The organic layer was separated, washed with saturated aqueous sodiumhydrogen carbonate (5 ml), brine (5 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether, 1:3, v/v) affordedthe title compound (20 mg, 32%) as a colourless oil. δ_(H)(COCl₃) 0.19(6H, s), 0.26 (6H, s), 0.94 (9H, s), 1.03 (9H, s), 1.68-1.88 (8H, m),3.00 (1H, m), 4.73 (1H, m), 6.29 (1H, d), 6.37 (1H, dd), 6.93 (1H, d),7.40-7.49 (3H, m); 7.63 (2H, m) and 7.88-7.97 (4H, m).

Preparation 34 cis-N-Benzoyloxy-N[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-(triflurormethyl)benzamide

[0279] Preparation 34 was prepared according to General Procedure Aabove fromcis-O-benzoyl-N-[4-2,4-bis{[tert-butyl(dimethy)silyl]oxy}phenyl)cyclohexyl]hydroxylamine(0.075 g) and 4-(trifluoromethyl)benzoyl chloride (0.04 ml) to give thetitle compound as a colourless oil (58 mg, 59%). δ_(H) (CDCl₃) 0.17 (6H,s), 0.22 (6H, s), 0.94 (9H, s), 1.00 (9H, s), 1.70-1.88 (8H, m), 2.97(1H, m), 4.69 (1H, m), 6.30 (2H, m), 6.88 (1H, d), 7.46 (2H, m), 7.62(3H, m), 7.78 (2H, d) and 7.92 (2H, d).

Preparation 35cis-N-Benzoyloxy-N[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4-methoxybenzamide

[0280] Preparation 35 was prepared according to General Procedure Aabove fromcis-O-benzoyl-N[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine(0.075 g) and p-anisoyl chloride (0.046 g) to give the title compound(33 mg, 35%) as a colourless oil. δ_(H) (CDCl₃) 0.20 (6H, s), 0.26 (6H,s), 0.94 (9H, s), 1.00 (9H, s), 1.70-1.97 (8H, m), 2.98 (1H, m), 3.78(3H, s), 4.68 (1H, s), 6.27 (1H, d), 6.33 (1H, dd), 6.83 (2H, d), 6.93(1H, d), 7.44 (2H, t), 7.60 (1H, t), 7.68 (2H, m) and 7.97 (2H, m).

Preparation 36 (±)-Methyl[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene] Acetate

[0281] To a flask was charged sodium hydride (60% dispersion in mineraloil) (83 mg) and THF (75 ml) and the mixture cooled to 0° C.Trimethylphosphonoacetate (0.28 ml) was added and the reaction mixturestirred for 1 hr at room temperature before adding a solution of4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanone (0.75 g)in THF (15 ml), and the mixture heated under reflux for 45 min. Thereaction mixture was cooled to room temperature, poured into saturatedammonium chloride solution (100 ml) and extracted with ethyl acetate(3×100 ml). The combined organic extracts were washed with brine (50ml), dried over magnesium sulfate, filtered and concentrated in vacuo.Purification via flash chromatography (SiO₂, petroleum ether) affordedthe title compound (0.57 g, 67%) as a colourless solid. δ_(H) (CDCl₃)0.22 (6H, s), 0.31 (6H, s), 1.03 (9H, s), 1.13 (9H, s), 1.49-1.66 (2H,m), 1.97-2.08 (4H, m), 2.33-2.51 (2H, m), 3.20 (1H, m), 3.73 (3H, s),5.73 (1H, s), 6.38 (1H, d), 6.44 (1H, dd) and 7.03 (1H, d).

Example 1 4(1,4-Dioxaspiro[4.5]dec-8-yl)-1,3-benzenediol

[0282] A round bottomed flask was charged with5-benzyloxy-21,4-dioxaspiro[4.5]dec-7-en-8-yl)phenol (6.90 g), ethanol(300 ml) and palladium (2.00 g, 10%,on activated carbon). The reactionvessel was then evacuated and placed under a hydrogen atmosphere. Thisprocess was repeated 15 times before stirring vigorously for 64 hr undera hydrogen atmosphere. The reaction mixture was filtered through acelite plug, washing with ethyl acetate. The filtrate was concentratedin vacuo, furnishing the title compound (5.10 g, 100%) as a solid.δ_(H)(CD₃OD) 1.65-1.87 (8H, m), 2.86-2.90 (1H, m), 3.90-4.06 (4H, m),6.27 (1H, dd), 6.29 (1H, d), 6.92 (1H, d); m/z (ES⁺) 251 (M+H⁺).

Example 2 (±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic Acid

[0283] A round bottomed flask was charged with(±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetic acid (25mg), acidic Dowex resin (75 mg) and methanol (15 ml) then stirred at 60°C. for 3 hr. The reaction mixture was filtered through a celite plug,washing with methanol. The solvent was removed under reduced pressure togive an oil which was purified by preparative TLC (ethylacetate/petroleum ether, 3:1, v/v), furnishing the title compound (6.5mg, 35%) as an oil. δ_(H)(CD₃OD) 1.22-1.40 (2H, m), 1.90-2.10 (4H, m),2.36-2:40 (2H, m), 3.08 (1H, tt), 5.62 (1H, s), 6.20 (1H, dd), 6.25 (1H,d), 6.84 (1H, d); m/z (ES⁺) 339 (M+H⁺).

Example 3 (±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile

[0284] To a round bottomed flask was added(±)-{4-[2,4-bis(methoxymethoxy)phenyl]cyclohexylidene}acetonitrile (141mg) and methanol (5 ml). The reaction mixture was stirred, the solutionwas heated under reflux temperature and aqueous hydrochloric acid (5 ml,1.0M) was added slowly. Heating was continued for 1 hr and the reactionmixture was allowed to cool to room temperature prior to the addition ofsaturated aqueous sodium bicarbonate solution (12 ml). The reactionmixture was partitioned between ethyl acetate (30 ml) and water (10 ml).The aqueous layer was extracted with ethyl acetate (3×15 ml) and thecombined organic layers washed with brine (20 ml), dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purifiedvia flash column chromatography (SiO₂, ethyl acetate/petroleum ether,1:1, v/v) to afford the title compound (90 mg, 88%) as a white solid.m/z (ES⁻) 228 (M−H⁺); SH(CD₃OD) 1.56-1.68 (2H, m), 2.02-2.14 (2H, m),2.33-2.48 (2H, m), 2.57 (1H, m), 3.01 (1H, m), 3.14 (1H, m), 5.31 (1H,s), 6.27 (1H, dd), 6.32 (1H, d), 6.80 (1H, d).

Example 4 cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide

[0285] A round bottomed flask was charged withcis-O-benzoyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine,(0.04 g), dichloromethane (2 ml), triethylamine (0.05 ml) and benzoylchloride (0.025 ml). After stirring for 0.5 hr, the mixture was dilutedwith dichloromethane (15 ml) and washed with 2M HCl (5 ml). The organiclayer was separated, washed with saturated aqueous sodium hydrogencarbonate (5 ml), brine (5 ml), dried over magnesium sulfate, filteredand concentrated in vacuo affording a crystalline solid. This solid wasdissolved in ethanol (2 ml) and sodium hydroxide (2M, 0.25 ml) added.After stirring overnight, the solution was concentrated in vacuo,diluted with water (2 ml) and extracted with ethyl acetate (5 ml). Theaqueous layer was separated, acidified with 2M HCl and extracted withethyl acetate (3×5 ml). The combined organic phases were washed withbrine (5 ml), dried over magnesium sulfate, filtered and concentrated invacuo. Purification via flash chromatography (SiO₂, ethylacetate/petroleum ether, 2:1, v/v) afforded the title compound (0.013 g,55%) as an off-white powder. δ_(H) (CD₃OD) 1.68-1.82 (4H, m), 2.03-2.18(4H, m), 3.01 (1H, m), 4.40 (1H, m), 6.20-6.26 (2H, m), 7.02 (1H, d),7.38-7.50 (3H, m) and 7.60 (2H, m); m/s(ES⁺) 328.16 (M+H)⁺.

Example 5 cis-N-[4(2,4-Dihydroxyphenyl)cyclohexyl]benzamide

[0286] A solution ofcis-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]benzamide(0.08 g) in methanol (2 ml) was stirred rapidly with Amberlyst A-26(fluoride resin) (0.25 g) for 17 hr. The mixture was filtered through apad of celite and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether, 3:1, v/v) affordedthe title compound (0.025 g, 54%) as a colourless solid. δ_(H) (CD₃OD)1.70-1.91 (6H, m), 1.98-2.10 (2H, m), 2.88 (1H, m), 4.23 (1H, m),6.21-6.30 (2H, m), 6.99 (1H, d), 7.40-7.57 (3H, m) and 7.81 (2H, d);m/s(ES⁺) 312.13 (M+H)⁺.

Example 6trans-4-{4-[(Z)-benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol

[0287]cis-O-Benzoyl-Nbenzyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl] hydroxylamine (50 mg) was dissolved in a mixture of methanol (1ml) and THF (2 ml) and sodium hydroxide (2M, 0.4 ml) was added withstirring. After 2 hr, the solution was acidified with 2M HCl andextracted with ethyl acetate (3×11 ml). The combined organic extractswere washed with saturated aqueous sodium hydrogen carbonate (5 ml),brine (5 ml), dried over magnesium sulfate, filtered and concentrated invacuo. Purification via flash chromatography (SiO₂, ethylacetate/petroleum ether, 3:1, v/v) afforded the title compound (2 mg,8%) as colorless crystals. oil. δ_(H) (CD₃OD) 1.60-1.72 (2H, m), 2.00(2H, m), 2.08-2.12 (4H, m), 2.88 (1H, m), 4.13 (1H, m), 6.23 (1H, dd),6.26 (1H, d), 6.91 (1H, d), 7.47 (3H, m), 7.96 (1H, s) and 8.28 (2H, m);m/s(ES⁺) 312.16 (M+H)⁺.

Example 7 trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide

[0288] A round bottomed flask was charged withtrans-benzoyl-N-[4-2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]hydroxylamine(0.16 g), dichloromethane (3 ml), triethylamine (0.05 ml) and benzoylchloride (0.05 ml). After stirring for 1 hr, the mixture was dilutedwith dichloromethane (15 ml) and washed with 2M HCl (5 ml). The organiclayer was separated, washed with saturated aqueous sodium hydrogencarbonate (5 ml), brine (5 ml), dried over magnesium sulfate, filteredand concentrated in vacuo affording a crystalline solid. This solid wasdissolved in methanol (2 ml) and stirred rapidly with Amberlyst A-26(fluoride resin) (0.5 g) for 24 hr. The mixture was filtered through apad of celite and concentrated in vacuo. This residue was dissolved inethanol (2 ml) and sodium hydroxide (2M, 0.5 ml) added with stirring.After stirring for 10 min the solution was acidified with 2M HCl,diluted with water (2 ml) and extracted with ethyl acetate (3×10 ml).The combined organic extracts were washed with brine (5 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether, 3:1, v/v)afforded the title compound (0.025 g, 20%) as a yellow powder. δ_(H)d₆-DMSO (45° C.) 1.38-1.52 (2H, m), 1.76-1.89 (6H, m), 2.84 (1H, m),4.22 (1H, m), 6.16 (1H, dd), 6.23 (1H, d), 6.81 (1H, d), 7.38 (3H, m),7.59 (2H, m), 8.80 (1H, s), 8.90 (1H, s) and 9.38 (1H, s); m/s(ES⁺)328.60 (M+H)⁺, 369.59 (MH+MeCN)⁺.

Example 8 syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one

[0289] A solution ofsyn-8-(2,4-bis{[tert-Butyl(dimethylsilyl)]oxy}phenyl-1-oxaspiro[4.5]decan-2-one(0.04 g) in methanol (4 ml) was stirred rapidly with Amberlyst A-26(fluoride resin) (0.2 g) for 17 hr. Acetic acid (0.5 ml) was added andstirring continued for a further 1 hr. The mixture was then filteredthrough a pad of celite and concentrated in vacuo. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether, 2:1, v/v)afforded the title compound (0.007 g, 33%) as a colourless oil. δ_(H)(CD₃OD) 1.53-1.68 (2H, m), 1.80-1.95 (6H, m), 2.23 (2H, t), 2.86 (2H,t), 2.84 (1H, m), 6.22 (1H, dd), 6.25 (1H, d) and 6.88 (1H, d); m/s(ES⁺)304.17 (MH+MeCN)⁺.

Example 9 cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea

[0290] A solution of phenylisocyanate (0.015 ml, 0.13 mmol),triethylamine (0.03 ml), 4-dimethylaminopyridine (catalytic) andcis-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine(0.043 g) in dichloroethane (4 ml) was stirred at room temperature for17 hr. The mixture was partitioned between saturated aqueous sodiumhydrogen carbonate (5 ml) and dichloromethane (5 ml). The aqueous phasewas extracted with dichloromethane (2×5 ml) and the combined organicextracts washed with brine (7 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. The resulting oil was dissolved indichloromethane (6 ml) and stirred rapidly with water (3 ml) andtrifluoroacetic acid (3 ml) for 60 hr. Toluene (15 ml) was added and thesolution concentrated in vacuo. Purification via flash chromatography(SiO₂, ethyl acetate/petroleum ether) afforded the title compound (0.013g, 30%) as a colourless solid. δ_(H) (CD₃OD) 1.32-1.46 (2H, m),1.53-1.69 (2H, m), 1.90 (2H, m), 2.17 (2H, m), 2.83 (1H, m), 3.65 (1H,m), 6.28 (2H, m), 6.94 (1H, d), 7.00 (1H, m), 7.27 (2H, m) and 7.38 (2H,m); m/s(ES⁺) 327.20 (M+H)⁺.

Example 10 trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate

[0291] A solution of phenylchloroformate (0.045 ml, 0.36 mmol),triethylamine (0.085 ml), 4-dimethylaminopyridine (catalytic) andtrans-4(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexylamine(0.043 g) in dichloroethane (11 ml) was stirred at room temperature for60 hr. The mixture was partitioned between saturated aqueous sodiumcarbonate (15 ml) and dichloromethane (15 ml). The aqueous phase wasextracted with dichloromethane (2×15 ml) and the combined organicextracts washed with brine (20 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether) afforded acolourless gum. This was dissolved in dichloromethane (15 ml) and warmedwith a mixture of water (7.5 ml) and trifluoroacetic acid (7.5 ml) at80° C. for 17 hr. On cooling, toluene (25 ml) was added and the solutionconcentrated in vacuo. Methanol (25 ml) was added and the solution againconcentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether) afforded the title compound (0.013 g,13%) as a colourless solid. δ_(H) (CD₃OD) 1.44-1.63 (4H, m), 1.96 (2H,m), 2.13 (2H, m), 2.86 (1H, m), 3.55 (1H, m), 6.30 (2H, m), 6.92 (1H,d), 7.12 (2H, m), 7.22 (1H, m) and 7.40 (2H, m); m/s(ES⁺) 328.26 (M+H)⁺.

Example 11cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea

[0292] A solution of ethylisocyanate (0.038 ml, 0.48 mmol),triethylamine (0.065 ml) andcis-N-benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine(0.122 g) in dichloroethane (10 ml) was stirred at room temperature for60 hr. The reaction mixture was partitioned between water (10 ml) anddichloromethane (10 ml). The aqueous layer was separated and extractedwith dichloromethane (2×10 ml) and the combined organic extracts washedwith brine (10 ml), dried over magnesium sulfate, filtered andevaporated in vacuo. The resulting residue was dissolved indichloromethane (15 ml) and warmed with a mixture of water (7.5 ml) andtrifluoroacetic acid (7.5 ml) at 80° C. for 17 hr. Toluene (25 ml) wasthen added and the mixture concentrated in vacuo. Methanol (25 ml) wasthen added and the mixture again concentrated in vacuo. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether) afforded thetitle compound (0.016 g, 19%) as a colourless solid. δ_(H) (CD₃OD) 1.08(3H, t), 1.57-1.88 (6H, m), 2.12 (2H, m), 3.16 (1H, m), 3.24 (2H, m),4.17 (1H, m), 4.52 (2H, s), 6.09 (1H, t), 6.24 (1H, dd), 6.29 (1H, d),6.98 (1H, d) and 7.22-7.37 (5H, m). m/s(ES⁺) 369.54 (M+H)⁺.

Example 12 cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide

[0293]cis-N-Benzyl-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]amine (0.084 g) was dissolved in dichloroethane (7 ml), andtriethylamine (0.045 ml) and 4-dimethylaminopyridine (catalytic) added.Propionyl chloride (0.028 ml) was then added, and the mixture stirred atroom temperature for 60 hr. The reaction mixture was partitioned betweendichloromethane (10 ml) and saturated aqueous sodium hydrogen carbonate(10 ml). The aqueous layer was extracted with dichloromethane (2×10 ml)and the combined organic extracts washed with brine (10 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue wasdissolved with stirring in dichloroethane (16 ml) and heated with amixture of water (10 ml), methanol (5 ml) and trifluoroacetic acid (10ml) at 80° C. for 17 hr. Toluene (25 ml) was then added and the mixtureconcentrated in vacuo. Methanol (25 ml) was then added and the mixtureagain concentrated in vacuo. Purification via flash chromatography(SiO₂, ethyl acetate/petroleum ether) afforded the title compound (0.021g, 37%) as a colourless solid. R_(f) 0.20 (ethyl acetate/petroleumether, 1:1, v/v); m/s(ES⁺) 354.17 (M+H)⁺.

Example 13 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl phenylcarbamate

[0294]trans-4-(2,4-Bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylphenylcarbamate(55 mg) and fluoride resin (300 mg) were stirred in methanol (10 ml) atroom temperature. After 16 hr, the reaction mixture was filtered througha pad of celite, which was washed with a copious volume of methanol. Thefiltrate was concentrated in vacuo and the residue was purified by flashcolumn chromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to give thetitle compound (17 mg, 60%) as an orange solid. δ_(H) (CD₃OD) 1.20-1.30(1H, m), 1.40-1.60 (4H, m), 1.80-2.20 (3H, m), 2.75-2.90 (1H, m),3.20-3.40 (1H, m), 4.60-4.80 (1H, m), 6.20-6.30 (2H, m), 6.90-7.00 (2H,m), 6.20-6.30 (2H, m), 7.30-7.40 (2H, m); m/z (ES⁺) 328 (M+H⁺).

Example 14trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate

[0295] N,N-Diisopropylethylamine (398 μl) and ethylisocyanoacetate (154μl) were added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (200mg) in anhydrous dimethylformamide (1 ml). After 16 hr at 50° C., thereaction mixture was partitioned between ethyl acetate (50 ml) and water(50 ml) and stirred for 16 hr at room temperature. The aqueous layer wasextracted with ethyl acetate (2×50 ml). The combined organic extractswere washed with brine (50 ml), dried over magnesium sulfate andevaporated in vacuo. The residue was purified using flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to give the titlecompound (70 mg, 70%) as a pale yellow gum. δ_(H) (CD₃OD) 1.30-1.40 (3H,m), 1.50-1.70 (3H, m), 1.88-2.24 (4H, m), 2.76-2.90 (1H, m), 3.90 (2H,s), 4.10-4.30 (3H, m), 4.58-4.70 (1H, m), 6.26-6.32 (2H, m), 6.94 (1H,d); m/z (ES⁺) 338 (M+H⁺).

Example 15 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate

[0296] N,N-Diisopropylethylamine (398 μl) and benzylisocyanate (154 μl)was added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (200mg) in anhydrous dimethylformamide (1 ml). After 16 hr at 50° C., thereaction mixture was partitioned between ethyl acetate (50 ml) and water(50 ml) and stirred for 16 hr at room temperature. The aqueous layer wasextracted with ethyl acetate (2×50 ml). The combined organic extractswere washed with brine (50 ml), dried over magnesium sulfate andevaporated in vacuo. The residue was purified using flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:1 v/v) to give the titlecompound (20 mg, 13%) as a pale yellow gum. δ_(H) (CD₃OD) 1.40-1.60 (4H,m), 1.80-1.90 (2H, m), 1.00-1.20 (2H, m), 2.70-2.82 (1H, m), 4.20-4.30(2H, s), 4.55-4.65 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d), 7.15-7.40(5H, m); m/z (ES⁺) 342 (M+H⁺).

Example 16 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl Ethyl Carbonate

[0297] Triethylamine (0.5 ml), ethylchloroformate (0.5 ml) anddimethylaminopyridine (cat.) were added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250mg) in anhydrous dichloromethane (5 ml). After 72 hr at roomtemperature, the reaction mixture was partitioned between-ethyl-acetate(50 ml) and water (50 ml). The aqueous layer was extracted with ethylacetate (2×50 ml). The combined organic extracts were washed with brine(50 ml), dried over magnesium sulfate and evaporated In vacuo. Theresidue was dissolved in methanol (5 ml) and was stirred with fluorideresin (500 mg) for 16 h at room temperature. The resin was filteredthrough a pad of celite, which was washed well with methanol. Thecombined filtrates were concentrated in vacuo. The residue was purifiedusing flash column chromatography (SiO₂, ethyl acetate/petrol, 1:2 v/v),and then preparative HPLC to give the title compound (4 mg, 3%) as acream solid. δ_(H) (CD₃OD) 1.20-1.30 (3H, m), 1.40-1.60 (4H, m),1.80-1.95 (2H, m), 2.00-2.20 (2H, m), 2.70-2.84 (1H, m), 4.06-4.20 (2H,m), 4.50-4.60 (1H, m), 6.20-6.30 (2H, m), 6.86 (1H, d); m/z (ES⁻) 279(M−H⁻).

Example 17trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate

[0298] N,N-Diisopropylethylamine (6.0 ml) and ethylisocyanoacetate (3.6ml) were added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (3.0g) in anhydrous dimethylformamide (10 ml). After 16 hr at 50° C., thereaction mixture was partitioned between ethyl acetate (300 ml) andwater (300 ml). The aqueous layer was extracted with ethyl acetate(2×300 ml). The combined organic extracts were washed with brine (100ml), dried over magnesium sulfate and evaporated in vacuo. The residuewas dissolved in methanol (100 ml) and was stirred with fluoride resin(2 g) for 16 hr at room temperature. The suspension was filtered througha pad of celite, which was washed well with methanol. The combinedfiltrates were concentrated in vacuo and the residue was purified usingflash column chromatography (SiO₂, ethyl acetate/petrol, 1:3 v/v) togive the title compound (812 mg, 37%) as a pale yellow gum. δ_(H)(CD₃OD) 1.45-1.55 (4H, m), 1.80-1.90 (2H, m), 2.00-2.10 (2H, m),2.70-2.80 (1H, m), 3.70 (3H, s), 3.80 (2H, s), 4.50-4.64 (1H, m),6.00-6.25 (2H, m), 6.9 (1H, d); m/z (ES⁺) 324 (M+H⁺).

Example 18 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methylImidodicarbonate

[0299] N,N-Diisopropylethylamine (497 μl) and ethylisocyanatoformate(177 μl) were added to a stirred solution oftrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol (250mg) in anhydrous dimethylformamide (2 ml). After 120 hr at 50° C., thereaction mixture was partitioned between ethyl acetate (50 ml) and water(50 ml). The aqueous layer was extracted with ethyl acetate (2×50 ml).The combined organic extracts were washed with brine (50 ml), dried overmagnesium sulfate and evaporated in vacuo. The residue was dissolved inmethanol (10 ml) and was stirred with fluoride resin (300 mg) for 16 hrat room temperature. The suspension was filtered through a pad ofcelite, which was washed well with methanol. The combined filtrates wereconcentrated in vacuo and the residue was purified using flash columnchromatography (SiO₂, ethyl acetate/petrol, 1:3 v/v) and thenpreparative HPLC to give the title compound (4 mg, 2%) as a pale yellowgum. 5. (CD₃OD) 1.20-1.40 (4H, m), 1.55 (3H, t), 1.80-1.90 (2H, m),2.00-2.18 (2H, m), 2.72-2.82 (1H, m), 4.20 (2H, q), 6.20-6.25 (2H, m),6.84 (1H, d); m/z (ES⁻) 322 (M−H⁻).

Example 19 cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol

[0300] A stirred suspension of dimethylsulfoxide (17 ml) and sodiumhydride (0.69 g, 60% dispersion in mineral oil) was heated to 70° C.under argon. After 1 hr, the solution was cooled to room temperature andwas added to a solution of trimethylsulfonium iodide (1.5 g) indimethylsulfoxide (8 ml) added at 0° C. A solution of4-(2,4-dihydroxyphenyl)cyclohexanone (1.0 g) in anhydroustetrahydrofuran (15 ml) was added over 0.1 hr. After stirring at roomtemperature for 16 hr, the reaction mixture was partitioned betweensaturated ammonium acetate solution (150 ml) and ethyl acetate (150 ml).The layers were separated and the aqueous layer was extracted with ethylacetate (4×50 ml). The combined organic extracts were washed with brine(50 ml), dried over magnesium sulfate and concentrated in vacuo. Theresidue was purified by flash column chromatography to give the title asa white solid (316 mg, 30%). δ_(H) (CD₃OD) 1.20-1.40 (2H, m), 1.60-2.10(6H, m), 2.66 (1.4H, s), 2.69 (0.6H, s), 2.75-2.95 (1H, m), 6.20-6.27(2H, m), 6.90 (0.7H, d), 6.91 (0.3H, d); m/z (ES⁻) 219 (M−H⁻).

Example 20 4-(4-Methylenecyclohexyl)-1,3-benzenediol

[0301] To a round bottomed flask was addedtert-butyl[5-{[tert-butyl(dimethyl)silyl]oxy}-2-(4-methylenecyclohexyl)phenoxy]dimethylsilane(40 mg), tetrahydrofuran (2 ml) and tetrabutylammonium fluoride (281 μl,1.0M in tetrahydrofuran), and the mixture stirred at room temperaturefor 15 hr. The solvent was removed in vacuo and the residue partitionedbetween water (20 ml) and ethyl acetate (20 ml). The aqueous phase wasextracted with ethyl acetate (2×20 ml), and the combined organic phaseswere washed with brine (20 ml), dried over magnesium sulfate, filteredand concentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether 2:3 v/v) furnished the title compound (17mg, 90%) as a white solid. δ_(H) (CD₃OD): 1.42-1.53 (2H, m), 1.90-1.99(2H, m), 2.19-2.29 (2H, m), 2.39-2.47 (2H, m), 3.02 (1H, tt), 4.67 (2H,s), 6.28 (1H, dd), 6.31 (1H, d), 6.89 (1H, d); m/z (ES⁺) 205 (M+H)⁺.

Example 21 4-(3-Cyclohexen-1-yl)-1,3-benzenediol

[0302] To a round bottomed flask was addedcis/trans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexanol(208 mg) and dichloromethane (3 ml). The resulting solution was cooledto −78° C., and diethylaminosulfur trifluoride (69 μl) added in oneportion. The reaction mixture was allowed to warm to room temperatureand stirred for 15 hr. The reaction mixture was partitioned betweenwater (10 ml) and dichloromethane (20 ml), the layers were separated andthe aqueous phase was extracted with dichloromethane (3×20 ml). Thecombined organic phases were washed with brine (20 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. The crude oil wasdissolved in tetrahydrofuran (3 ml) and tetrabutylammonium fluoride(0.81 ml, 1.0M in tetrahydrofuran) and stirred at room temperature for15 hr. The reaction mixture was partitioned between water (10 ml) andethyl acetate (20 ml) and the layers were separated. The aqueous phasewas extracted with ethyl acetate (3×20 ml) and the combined organicphases were washed with brine (10 ml), dried over magnesium sulfate,filtered and concentrated in vacuo. Purification via flashchromatography (SiO₂, ethyl acetate/petroleum ether, 3:7 v/v) furnishedthe title compound (34 mg, 38%) as an off-white solid. δ_(H) (CD₃OD):1.69-1.86 (2H, m), 2.00-2.19 (4H, m), 3.09 (1H, tt), 5.67-5.80 (2H, m),6.16 (1H, d), 6.20 (1H, dd), 6.91 (1H, d); m/z (ES⁻) 189 (M−H)⁻.

Example 22 trans-4-(2,4-Dihydroxyphenyl)cyclohexyl(2R)-2-amino-3-phenylpropanoate

[0303] To a round bottomed flask was addedtrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl) cyclohexyl(2R)-2-[(tert-butoxycarbonyl)amino]-3-phenyl propanoate (250 mg),dichloromethane (10 ml), trifluoroacetic acid (4 ml) and water (0.5 ml).After stirring at room temperature for 15 hr, saturated sodium hydrogencarbonate solution (5 ml) was added, followed by water (10 ml) and ethylacetate (30 ml). The layers were separated and the aqueous layer wasextracted with ethyl acetate (2×30 ml), and the combined organic phaseswere washed with brine (15 ml), dried over magnesium sulfate, filteredand concentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/ammonia, 99:1 v/v) furnished the title compound (93 mg,72%) as an off-white solid. 5H (CD₃OD): 1.45-1.66 (4H, m), 1.85-2.15(4H, m), 2.76-2.88 (1H, m), 3.23 (2H, d), 3.97 (1H, t), 4.84-5.00 (1H,m), 6.27 (1H, dd), 6.32 (1H, d), 6.92 (1H, d), 7.28-7.45 (5H, m); m/z(ES⁺) 356 (M+H)⁺.

Example 23 Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate

[0304] To a round bottomed flask equipped with magnetic stirrer wasadded benzyl[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]acetate(232 mg), tetrahydrofuran (5 ml), tetrabutylammonium fluoride hydrate(429 mg) and glacial acetic acid (94 μl). After stirring at roomtemperature for 0.5 hr, the solvent was removed in vacuo and the residuepartitioned between ethyl acetate (100 ml) and water (20 ml). The layerswere separated and the aqueous phase was extracted with ethyl acetate(50 ml). The combined organic phases were washed with water (50 ml),brine (20 ml), dried over magnesium sulfate, filtered and concentratedin vacuo. Purification via flash chromatography (SiO₂, ethylacetate/petroleum ether, 1:3 v/v) furnished the title compound (100 mg,72%) as a cream solid. δ_(H) (CD₃OD): 1.59-1.67 (2H, m), 1.98-2.13 (4H,m), 2.37-2.48 (2H, m), 3.14 (1H, ft), 5.16 (2H, s), 5.75 (1H, s), 6.26(1H, dd), 6.30 (1H, d), 6.89 (1H, d), 7.30-7.44 (5H, m); m/z (ES⁻) 337(M−H)⁻.

Example 24 4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol

[0305] To a round bottomed flask equipped with magnetic stirrer wasadded 4-(2,4-dihydroxyphenyl)cyclohexanone (1 g) and toluene (40 ml). Tothe stirred solution was added ethane-1,2-dithiol (0.49 ml) and a fewcrystals of ptoluenesulfonic acid monohydrate and the reaction mixturewas heated under reflux for 3.5 hr. The reaction mixture was cooled toroom temperature, saturated sodium hydrogencarbonate solution (20 ml)was added, and the layers were separated. The aqueous layer was dilutedwith water (40 ml) and extracted into ethyl acetate (3×30 ml). Thecombined organic phases were washed with brine (30 ml), dried overmagnesium sulfate, filtered and concentrated in vacuo. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether 2:3 v/v)furnished the title compound (1.34 g, 98%) as a white solid. δ_(H)(CD₃OD): 1.59-1.73 (2H, m), 1.75-1.84 (2H, m), 1.98-2.08 (2H, m),2.14-2.22 (2H, m), 2.77 (1H, tt), 3.22-3.32 (4H, m), 6.18-6.24 (2H, m),6.85 (1H, d); m/z (ES⁺) 283 (M+H)⁺.

Example 25N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide

[0306] To a round bottomed flask was addedN′-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene-4-methylbenzenesulfonohydrazide(100 mg), tetrahydrofuran (5 ml), glacial acetic acid (3 drops) andtetrabutylammonium fluoride hydrate (174 mg), and the resulting solutionwas stirred at room temperature for 2 hr. Saturated sodium hydrogencarbonate solution (10 ml) was added and stirring was continued for 1hr. The reaction mixture was partitioned between water (10 ml) and ethylacetate (20 ml), the layers were separated, and the aqueous phase wasextracted with ethyl acetate (2×20 ml). The combined organic phases werewashed with brine (10 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether, 7:3 v/v) furnished the title compound (62mg, 100%) as a cream solid. δ_(H) ((CD₃)₂CO): 1.44-1.63 (2H, m),1.92-2.01 (3H, m), 2.22-2.32 (1H, m), 2.35-2.43 (2H, m), 2.97 (3H, s),3.09 (1H, tt), 6.28 (H, dd), 6.37 (1H, d), 6.87(1H, d), 7.38 (2H, d),7.79 (2H, d), 7.96 (1H, s), 8.13 (1H, s), 8.99 (1H, s); m/z (ES⁺) 375(M+H)⁺.

Example 26 trans-N-[4(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide

[0307] To a round bottomed flask was addedtrans-N-[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy})cyclohexyl]-3-nitrobenzamide(52 mg), dichloroethane (9 ml), water (3 ml), and trifluoroacetic acid(3 ml). The reaction mixture was heated under reflux for 15 hr, cooledto room temperature, and toluene (15 ml) was added. The reaction mixturewas concentrated in vacuo, methanol (15 ml) was added, and furtherconcentrated to remove residual trifluoroacetic acid. Purification viaflash chromatography (SiO₂, ethyl acetate/petroleum ether, gradientelution using 1:3, then 1:1, v/v) furnished the title compound (20 mg,63%) as a white solid. δ_(H) ((CD₃)₂CO): 1.52-1.68 (4H, m), 1.87-1.95(2H, m), 2.09-2.17 (2H, m), 2.87 (1H, tt), 3.97-4.08 (1H, m), 6.30 (1H,dd), 6.38 (1H, d), 6.99 (1H, d), 7.77 (1H, t), 7.90 (1H, s), 7.96 (1H,d), 8.05 (1H, s), 8.33 (1H, dd), 8.37 (1H, dd), 8.68 (1H, t); m/z (ES⁺)357 (M+H)⁺.

Example 27 trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-phenylurea

[0308] To a round bottomed flask was addedtrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(750 μl, 0.114M in dichloromethane) and dichloroethane (3.5 ml). To thestirred solution was added phenylisocyanate (15 μl), triethylamine (30μl) and a few crystals of 4-dimethylaminopyridine, and the resultingsolution was stirred at room temperature for 15 hr. The mixture waspartitioned between water (5 ml) and dichloromethane (5 ml), the layersseparated, and the aqueous phase extracted with dichloromethane (2×5ml). The combined organic phases were washed with brine (7 ml), driedover magnesium sulfate, filtered and concentrated in vacuo to give abrown gum (57 mg). The residue was dissolved in dichloromethane (6 ml),methanol (3 ml), trifluoroacetic acid (3 ml) and water (3 ml), and theresulting solution was stirred at room temperature for 96 hr. Residualtrifluoroacetic acid was removed by co-evaporation with toluene (15 ml),then methanol (15 ml), in vacuo. Purification via flash chromatography(SiO₂, ethyl acetate/petroleum ether, gradient elution using 1:4, 2:3,then 3:2 v/v) furnished the title compound (10 mg, 31%) as a whitesolid. δ_(H) (CD₃OD): 1.44-1.64 (4H, m), 1.88-1.96 (2H, m), 2.08-2.16(2H, m), 2.86 (1H, tt), 3.47-3.58 (1H, m), 6.27 (1H, dd), 6.30 (1H, d),6.93 (1H, d), 7.13 (2H, d), 7.23 (1H, t), 7.41 (2H, t); m/z (ES⁺) 327(M+H)⁺.

Example 28trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide

[0309] To a round bottomed flask equipped was addedtrans-4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylamine(56 mg) and dichloroethane (5 ml). To the stirred solution were addedtrifluorbacetic anhydride (60 μl), triethylamine (40 μl) and a4-dimethylaminopyridine (catalytic), and the resulting solution washeated to 50° C. for 15 hr. The reaction mixture was partitioned betweenaqueous sodium hydroxide (10 ml, 0.5M) and dichloromethane (10 ml), thelayers separated, and the aqueous phase extracted with dichloromethane(2×10 ml). The combined organic phases were washed with brine (10 ml),dried over magnesium sulfate, filtered and concentrated in vacuo to givea gum. The residue was dissolved in dichloroethane (9 ml),trifluoroacetic acid (3 ml) and water (3 ml), and the resulting solutionwas heated under reflux for 15 hr. The reaction mixture was cooled toroom temperature and the residual trifluoroacetic acid removed byco-evaporation with toluene (10 ml), then methanol (10 ml), in vacuo.Purification via flash chromatography (SiO₂, ethyl acetate/petroleumether, gradient elution using 2:1 then 1:1 v/v) furnished the titlecompound (12 mg, 31%) as a white solid. δ_(H) ((CD₃)₂CO): 1.49-1.66 (4H,m), 1.85-1.93 (2H, m), 1.98-2.07 (2H, m), 2.78-2.89 (1H, m), 3.78-3.90(1H, m), 6.29 (1H, dd), 6.37 (1H, d), 6.95 (1H, d), 7.91 (1H, s), 8.06(1H, s), 8.18 (1H, br s); m/z (ES⁻) 302 (M−H)⁻.

Example 29cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide

[0310] General Procedure B

[0311]cis-N-Benzoyloxy-N-[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-3-cyanobenzamide(20 mg) was dissolved in methanol (2 ml) and stirred rapidly withAmberlyst A-26 (fluoride resin) (0.1 g) for 24 hr. The mixture wasfiltered through a pad of celite and concentrated in vacuo. This residuewas dissolved in ethanol (2 ml) and sodium hydroxide (2M, 0.2 ml) addedwith stirring. After stirring for 15 min, the solution was acidifiedwith 2M HCl, diluted with water (2 ml) and extracted with ethyl acetate(3×5 ml). The combined organic extracts were washed with brine (5 ml),dried over magnesium sulfate, filtered and concentrated in vacuo.Purification via flash chromatography (SiO₂, ethyl acetate/petroleumether, 2:1, v/v) afforded the title compound (0.004 g, 39%) as acolourless solid; δ_(H) (CD₃OH) 1.68-1.84 (4H, m), 2.03-2.17 (4H, m),3.03 (1H, m), 4.52 (1H, m), 6.24 (2H, m), 7.03 (1H, d), 7.61 (1H, t),7.80 (1H, m), 7.91 (1H, m) and 7.97 (1H, m). m/z (ES⁻) 351 (M−H)⁻, 397((M+HCO₂H)−1).

Example 30cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide

[0312] Example 30 was prepared according to General Procedure B abovefromcis-N-benzoyloxy-N-[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]-4(trifluoromethyl) benzamide (0.058 g) to give the title compound (0.017 g, 54%) asa colourless solid. δ_(H) (CD₃OH) 1.70-1.82 (4H, m), 2.01-2.18 (4H, m),3.03 (1H, m), 4.47 (1H, m), 6.22 (2H, m), 7.02 (1H, d), and 7.71-7.80(4H, m). m/z (ES⁺) 396 (M+H)⁺.

Example 31cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-methoxybenzamide

[0313] Example 31 was prepared according to General Procedure B abovefrom cis—N-benzoyloxy-N[2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexyl]methoxybenzamide (0.033 mg) to give the title compound (12 mg, 70%) as a colourlesssolid. δ_(H) (CD₃OH) 1.68-1.80 (4H, m), 2.00-2.19 (4H, m), 3.02 (1H, m),3.83 (3H, s), 4.42 (1H, m), 6.25 (2H, m), 6.97 (2H, d), 7.03 (1H, d),and 7.62 (2H, d). m/z (ES⁺) 358 (M+H)⁺.

Example 32 (±)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene] Acetate

[0314] To a stirred solution ofmethyl[4-(2,4-bis{[tert-butyl(dimethyl)silyl]oxy}phenyl)cyclohexylidene]acetate (0.035 g) in THF (10 ml) was addedtetrabutylammonium fluoride (0.14 ml). After 45 min, the mixture waspoured into saturated sodium carbonate solution (20 ml) and extractedwith ethyl acetate (3×20 ml). The combined organic extracts were washedwith brine (10 ml), dried over magnesium sulfate, filtered andconcentrated in vacuo. Purification via flash chromatography (SiO₂,ethyl acetate/petroleum ether, 1:1, v/v) afforded the title compound(0.015 g, 80%) as a white solid. oil. δ_(H) (CD₃OH) 1.50-1.68 (2H, m),1.98-2.13 (4H, m), 2.38-2.46 (2H, m), 3.14 (1H, m), 3.72 (3H, s), 5.72(1H, s), 6.36 (1H, dd), 6.30 (1H, d) and 6.90 (1H, d). m/z (ES⁻) 261(M−H)⁻.

[0315] Additional compounds (Examples 33-65) have also been prepared(Table 1, below). These compounds fall within the scope of the presentinvention, are useful in the pharmaceutical compositions and methods ofthe present invention, and can be prepared using the above-describedsynthetic processes in conjunction with standard techniques. TABLE 1Example Structure Information 33

m/z (ES+); 313 (M + H)⁺RT = 2.01 min. 34

m/z (ES−); 349 (M − H)⁻RT = 2.72 min. 35

m/z (ES+); 435 (M + H + DMSO)⁺RT = 2.65 min. 36

m/z (ES+); 405 (M + H + DMSO)⁺RT = 1.70 min. 37

m/z (ES+); 457 (M + H + DMSO)⁺RT = 2.55 min. 38

m/z (ES+); 391 (M + H + DMSO)⁺RT = 2.46 min. 39

m/z (ES+); 392 (M + H + DMSO)⁺RT = 2.73 min. 40

m/z (ES+); 448 (M + H + DMSO)⁺RT = 2.51 min. 41

m/z (ES+); 437 (M + H + DMSO)⁺RT = 2.45 min. 42

m/z (ES+); 456(M − H)⁻RT = 2.70 min. 43

m/z (ES−); 330 (M − H)⁻RT = 2.15 min. 44

m/z (ES−); 370 (M − H)⁻RT = 2.60 min. 45

m/z (ES−); 379 (M − H)⁻RT = 2.37 min. 46

m/z (ES−); 441 (M − H)⁻RT = 2.61 min. 47

m/z (ES+); 434 (M + H + DMSO)⁺Rt = 2.45 min. 48

m/z (ES+); 434 (M + H + DMSO)⁺RT = 2.43 min. 49

m/z (ES+); 410 (M + H + DMSO)⁺RT = 2.63 min. 50

m/z (ES+); 418 (M + H + DMSO)⁺RT = 2.54 min. 51

m/z (ES+); 404 (M + H + DMSO)⁺RT = 2.55 min. 52

m/z (ES−); 388 (M − H)⁻; 390 (M − H)⁻RT = 2.77 min. 53

m/z (ES−); 392 (M − H)⁻RT = 2.98 min. 54

m/z (ES−); 368 (M − H)⁻RT = 2.90 min. 55

m/z (ES+); 500 (M + H + DMSO)⁺; 502 (M + H + DMSO)⁺RT = 2.66 min. 56

m/z (ES−); 355 (M − H)⁻RT = 2.62 min. 57

m/z (ES+); 394 (M + H + DMSO)⁺RT = 2.57 min. 58

m/z (ES−); 378 (M − H)⁻RT = 2.81 min. 59

m/z (ES−); 381 (M + HCO₂)⁻RT = 2.52 min. 60

m/z (ES−); 436 (M − H)⁻RT = 2.80 min. 61

m/z (ES+); 468 (M + H + DMSO)⁺; 470 (M + H + DMSO)⁺RT = 2.54 min. 62

m/z (ES+); 468 (M + H + DMSO)⁺; 470 (M + H + DMSO)⁺RT = 2.75 min. 63

m/z (ES−); 422 (M − H); 424 (M − H)⁻RT = 2.77 min. 64

m/z (ES+); 405 (M + H)⁺RT = 2.51 min. 65

m/z (ES−); 454 (M − H)⁻RT = 2.61 min.

[0316] All patents, patent applications, and publications cited aboveare incorporated herein by reference in their entirety.

[0317] The present invention is not to be limited in scope by thespecific embodiments described herein, which are intended as singleillustrations of individual aspects of the invention, and functionallyequivalent methods and components are within the scope of the invention.Indeed, various modifications of the invention, in addition to thoseshown and described herein will become apparent to those skilled in theart from the foregoing description. Such modifications are intended tofall within the scope of the appended claims.

What is claimed is:
 1. A compound of formula i:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by—N(R¹)CONR²R³ wherein R¹ and R² are independently selected fromhydrogen, (C₁-C₆)alkyl, and aryl(C₁-C₆)alkyl, and R³ is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; —N(R⁴)COR⁵ wherein R⁴ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-, or OH and R⁵ is(C₇-C₁₀)alkyl, aryl, aryl(C₁-C₆)alkyl-, —O-aryl, CF₃, heterocycloalkyl,—(C₁-C₆)alkylheterocycloalkyl, —(C₂-C₇)alkenylheterocycloalkyl,heteroaryl, —(C₁-C₆)alkyl heteroaryl, —(C₂-C₇)alkenylheteroaryl,—(C₂-C₇)alkenylaryl, —(C₂-C₇)alkenylCOaryl, —(C₁-C₆)alkylN(R⁴)CO-aryl,—(C₁-C₆)alkylCO-aryl, —(C₁-C₆)alkylhydroxyaryl, —(C₁-C₆)alkyl-X-aryl,(C₂-C₇)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, ortetrahydronaphthalenyl, wherein X is O, S, SO, SO₂ or NR¹;—N(R¹)OCOaryl; ═CHCO₂R¹; ═CHCONR¹R²; ═CHCN; ═NNHSO₂R⁶ wherein R⁶ isaryl; —N(O)═CHR⁶; —OC(O)NR¹R⁷ wherein R⁷ is aryl, aryl(C₁-C₆)alkyl-,—(C₁-C₆)alkylCO₂(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl, —CO₂aryl, or—CO₂(C₁-C₆)alkylaryl; amino(C₁-C₆)alkylarylCO₂—; or —OC(O)OR⁸ wherein R⁸is (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; with the proviso that thecycloalkenyl ring is not aromatic.
 2. A compound of claim 1, wherein Ris substituted by —N(R¹)CONR²R³.
 3. A compound of claim 1, wherein R issubstituted by —N(R⁴)COR⁵.
 4. A compound of claim 1, wherein R issubstituted by —N(R¹)OCOaryl.
 5. A compound of claim 1, wherein R issubstituted by —NCHCO₂R¹.
 6. A compound of claim 1, wherein R issubstituted by ═CHCONR¹R².
 7. A compound of claim 1, wherein R issubstituted by ═CHCN.
 8. A compound of claim 1, wherein R is substitutedby ═NNHSO₂R⁶.
 9. A compound of claim 1, wherein R is substituted by—N(O)═CHR⁶.
 10. A compound of claim 1, wherein R is substituted by—OC(O)NR¹R₇.
 11. A compound of claim 1, wherein R is substituted byamino(C₁-C₆)alkylarylCO₂—.
 12. A compound of claim 1, wherein R issubstituted by —OC(O)OR⁸.
 13. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by ═CH₂; withthe proviso that the cycloalkenyl ring is not aromatic.
 14. A compoundof formula I:

or a pharmaceutically acceptable salt thereof, wherein R is3-cyclohexenyl.
 15. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl ring is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, So, SO₂ or NR¹, wherein R¹ is as defined above; Z isCH₂, O, S, SO or SO₂; m is 0-3; with the proviso that when m=0, then Zis CH₂; and with the proviso that the cycloalkenyl ring is not aromatic.16. A compound of formula I:

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₁-C₈)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl ring is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as defined above; and mis 0-3; and with the proviso that the cycloalkenyl ring is not aromatic.17. A compound selected from the group consisting of:4-(1,4-Dioxaspiro[4.5]decyl)-1,3-benzenediol;(±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;(±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;cis-N[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea;cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;4-(4-Methylenecyclohexyl)-1,3-benzenediol;4-(3-Cyclohexen-1-yl)-1,3-benzenediol;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate;Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide;cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxymethoxybenzamide;(±)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate; and apharmaceutically acceptable salt thereof.
 18. A pharmaceuticalcomposition for lightening skin or reducing the pigmentation of skin ina human, comprising a pharmaceutically acceptable carrier, and askin-lightening or pigmentation-reducing amount of a compound of formulaI:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl or (C₁-C₈)cycloalkenyl ring substituted by—N(R¹)CONR²R³ wherein R¹ and R² are independently selected fromhydrogen, (C₁-C₆)alkyl, and aryl(C₁-C₆)alkyl, and R³ is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; —N(R⁴)COR⁵ wherein R⁴ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-, or OH and R⁵ is(C₇-C₁₀)alkyl, aryl, aryl(C₁-C₆)alkyl-, —O-aryl, CF₃, heterocycloalkyl,—(C₁-C₆)alkylheterocycloalkyl, —(C₂-C₇)alkenylheterocycloalkyl,heteroaryl, —(C₁-C₆)alkyl heteroaryl, —(C₂-C₇)alkenylheteroaryl,—(C₂-C₇)alkenylaryl, —(C₂-C₇)alkenylCOaryl, —(C₁-C₆)alkylN(R⁴)CO-aryl,—(C₁-C₆)alkylCO-aryl, —(C₁-C₆)alkylhydroxyaryl, —(C₁-C₆)alkyl-X-aryl,(C₂-C₇)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, ortetrahydronaphthalenyl, wherein X is O, S, SO, SO₂ or NR¹;—N(R¹)OCOaryl; ═CHCO₂R¹; ═CHCONR¹R²; ═CHCN; ═NNHSO₂R⁶ wherein R⁶ isaryl; —N(O)═CHR⁶; —OC(O)NR¹R⁷ wherein R⁷ is aryl, aryl(C₁-C₆)alkyl-,—(C₁-C₆)alkylCO₂(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl, —CO₂aryl, or—CO₂(C₁-C₆)alkylaryl; amino(C₁-C₆)alkylarylCO₂—; or —OC(O)OR⁸ wherein R⁸is (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; with the proviso that thecycloalkenyl ring is not aromatic.
 19. A pharmaceutical composition forlightening skin or reducing the pigmentation of skin in a human,comprising a pharmaceutically acceptable carrier, and a skin-lighteningor pigmentation-reducing effective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by ═CH₂; withthe proviso that the cycloalkenyl ring is not aromatic.
 20. Apharmaceutical composition for lightening skin or reducing thepigmentation of skin in a human, comprising a pharmaceuticallyacceptable carrier, and a skin-lightening or pigmentation-reducingeffective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is3-cyclohexenyl.
 21. A pharmaceutical composition for lightening skin orreducing the pigmentation of skin in a human, comprising apharmaceutically acceptable carrier, and a skin-lightening orpigmentation-reducing effective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl ring is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as defined above; Z isCH₂, O, S, SO or SO₂; m is 0-3; with the proviso that when m=0, then Zis CH₂; and with the proviso that the cycloalkenyl ring is not aromatic.22. A pharmaceutical composition for lightening skin or reducing thepigmentation of skin in a human, comprising a pharmaceuticallyacceptable carrier, and a skin-lightening or pigmentation-reducingeffective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-CB)cycloalkyl or (C₅-CB)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl ring is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as defined above; and mis 0-3; and with the proviso that the cycloalkenyl ring is not aromatic.23. A pharmaceutical composition comprising a pharmaceuticallyacceptable carrier and a skin-lightening or pigmentation-reducingeffective amount of a compound selected from the group consisting of:4-(1,4-Dioxaspiro[4.5]decyl)-1,3-benzenediol;(±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;(±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-Phenyl-4-(2,4-dihydroxyphenyl)cyclohexylcarbamate;cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea;cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]propanamide;trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;4-(4-Methylenecyclohexyl)-1,3-benzenediol;4-(3-Cyclohexen-1-yl)-1,3-benzenediol;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate;Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]-4-methylbenzenesulfonohydrazide;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N[4(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide;cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-methoxybenzamide;(±)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate; and apharmaceutically acceptable salt thereof.
 24. A method of lighteningskin in a human, comprising administering to said human askin-lightening or pigmentation-reducing effective amount of a compoundof formula I:

or a pharmaceutically acceptable salt thereof, wherein: R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by—N(R¹)CONR²R³ wherein R¹ and R² are independently selected fromhydrogen, (C₁-C₆)alkyl, and aryl(C₁-C₆)alkyl, and R³ is hydrogen,(C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; —N(R⁴)COR⁵ wherein R⁴ ishydrogen, (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl-, or OH and R⁵ is(C₇-C₁₀)alkyl, aryl, aryl(C₁-C₆)alkyl-, —O-aryl, CF₃, heterocycloalkyl,—(C₁-C₆)alkylheterocycloalkyl, —(C₂-C₇)alkenylheterocycloalkyl,heteroaryl, —(C₁-C₆)alkyl heteroaryl, —(C₂-C₇)alkenylheteroaryl,—(C₂-C₇)alkenylaryl, —(C₂-C₇)alkenylCOaryl, —(C₁-C₆)alkylN(R⁴)CO-aryl,—(C₁-C₆)alkylCO-aryl, —(C₁-C₆)alkylhydroxyaryl, —(C₁-C₆)alkyl-X-aryl,(C₂-C₇)alkenyl, benzyhydryl, 5-hydroxyoxoindanyl, ortetrahydronaphthalenyl, wherein X is O, S, SO, SO₂ or NR¹;—N(R¹)OCOaryl; ═CHCO₂R¹; ═CHCONR¹R²; ═CHCN; ═NNHSO₂R⁶ wherein R⁶ isaryl; —N(O)═CHR⁶; —OC(O)NR¹R⁷ wherein R⁷ is aryl, aryl(C₁-C₆)alkyl-,—(C₁-C₆)alkylCO₂(C₁-C₆)alkyl, —CO₂(C₁-C₆)alkyl, —CO₂aryl, or—CO₂(C₁-C₆)alkylaryl; amino(C₁-C₆)alkylarylCO₂—; or —OC(O)OR⁸ wherein R⁸is (C₁-C₆)alkyl, aryl(C₁-C₆)alkyl, or aryl; with the proviso that thecycloalkenyl ring is not aromatic.
 25. A method of lightening skin in ahuman, comprising administering to said human a skin-lightening orpigmentation-reducing effective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring substituted by ═CH₂; withthe proviso that the cycloalkenyl ring is not aromatic.
 26. A method oflightening skin in a human, comprising administering to said human askin-lightening or pigmentation-reducing effective amount of a compoundof formula I,

or a pharmaceutically acceptable salt thereof, wherein R is3-cyclohexenyl.
 27. A method of lightening skin in a human, comprisingadministering to said human a skin-lightening or pigmentation-reducingeffective amount of a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-CS)cycloalkyl or (C₅-C₈)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl rings is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as defined above; Z isCH₂, O, S, SO or SO₂; m is 0-3; with the proviso that when m=0, then Zis CH₂; and with the proviso that the cycloalkenyl ring is not aromatic.28. A method of lightening skin in a human, comprising administering tosaid human a skin-lightening or pigmentation-reducing effective amountof a compound of formula I,

or a pharmaceutically acceptable salt thereof, wherein R is a(C₃-C₈)cycloalkyl or (C₅-C₈)cycloalkenyl ring, wherein one of the carbonatoms of said cycloalkyl or cycloalkenyl rings is substituted by twogroups such that the said groups are taken together with the carbon towhich they are attached to form a ring of the formula:

wherein X is O, S, SO, SO₂ or NR¹, wherein R¹ is as defined above; and mis 0-3; and with the proviso that the cycloalkenyl ring is not aromatic.29. A method of lightening skin in a human, comprising administering tosaid human a skin-lightening or pigmentation-reducing effective amountof a compound selected from the group consisting of:4-(1,4-Dioxaspiro[4.5]decyl)-1,3-benzenediol;(±)-{4-[2,4-Dihydroxyphenyl]cyclohexylidene}acetic acid;(±)-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]acetonitrile;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]benzamide;trans-4-{4-[(Z)benzylidene(oxido)amino]cyclohexyl}-1,3-benzenediol;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;syn-8-(2,4-Dihydroxyphenyl)-1-oxaspiro[4.5]decan-2-one;cis-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-Phenyl-4(2,4-dihydroxyphenyl)cyclohexylcarbamate;cis-N-Benzyl-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-ethylurea;cis-N-Benzyl-N-[4(2,4-dihydroxyphenyl)cyclohexyl]propanamide;trans-4-(2,4-Dihydroxyphenyl)cyclohexylphenylcarbamate;trans-Ethyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl benzylcarbamate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl ethyl carbonate;trans-Methyl[({[4-(2,4-dihydroxyphenyl)cyclohexyl]oxy}carbonyl)amino]acetate;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl methyl imidodicarbonate;cis/trans-4-(1-Oxaspiro[2.5]oct-6-yl)-1,3-benzenediol;4-(4-Methylenecyclohexyl)-1,3-benzenediol;4-(3-Cyclohexen-1-yl)-1,3-benzenediol;trans-4-(2,4-Dihydroxyphenyl)cyclohexyl (2R)-2-amino-3-phenylpropanoate;Benzyl [4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate;4-(1,4-Dithiaspiro[4.5]dec-8-yl)-1,3-benzenediol;N′-[4-(2,4-Dihydroxyphenyl)cyclohexylidene]4-methylbenzenesulfonohydrazide;trans-N-[4-(2,4-Dihydroxyphenyl)cyclohexyl]-3-nitrobenzamide;trans-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N′-phenylurea;trans-N-[4-(dihydroxyphenyl)cyclohexyl]-2,2,2-trifluoroacetamide;cis-3-cyano-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxybenzamide;cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxy-4-(trifluoromethyl)benzamide;cis-N-[4-(2,4-dihydroxyphenyl)cyclohexyl]-N-hydroxymethoxybenzamide;(±)-Methyl[4-(2,4-dihydroxyphenyl)cyclohexylidene]acetate; and apharmaceutically acceptable salt thereof.